Neolignan derivatives as platelet activating factor receptor antagonists and 5-lipoxygenase inhibitors

ABSTRACT

Neolignan derivative compounds of the 2,4-diaryl-1,3-dithiolane and futoenone variety exhibit both PAF and 5-lipoxygenase antagonist activity.

BACKGROUND OF THE INVENTION

This application is a 371 of PCT/US92/01830 filed Mar. 4, 1992.

1. Field of the Invention

The present invention is generally related to neolignan derivativeswhich inhibit both platelet activating factor and 5-lipoxygenase for thetreatment of inflammatory and allergic disorders.

2. Description of the Prior Art

Platelet activating factor (PAF) is a highly potent ether linkedphospholipid (1-O-alkyl-2-acetyl-sn-glycerol-3-phosphorylcholine) whichactivates platelets as well as modulates the function of leukocytes andother target cells. PAF has been shown to be a mediator of a variety ofpathophysiological conditions including arthritis, acute inflamation,asthma, endotoxic shock, pain, psoriasis, ophthalmic inflammation,ischemia, and gastrointestinal ulceration. Interaction with a specificmembrane recognition site coupled to phosphatidylinositol metabolismproduces the biological activity of PAF. Hence, blocking the PAFreceptor can provide beneficial medical results in human beings andmammals suffering from diseases or disorders mediated by PAF.

Several PAF antagonists have recently been synthesized or isolated fromnatural sources. For example, Shen et al. in Proc. Natl. Acad. Sci.(U.S.A.), 82. 672-678 (1985), reported that kadsurenone, a neolignanderivative isolated from Piper fotukadsura Sieb et Zucc (a Chineseherbal plant), was a potent, specific and competitive inhibitor of PAFat the receptor level. Biftu et al., in J. Med. Chem. 29, 1917 (1986),and Ponpipom et al., in Biochem. Bioshys. Res. Comm. 150, 1213 (1988),have shown that 2,5-diaryltetrahydrofurans L-652,731 and L-659,989 (bothof which are synthetic analogs of neolignan), respectively, are potentPAF receptor antagonists. U.S. Pat. No. 4,539,332 to Biftu et al. andU.S. Pat. No. 4,595,693 to Biftu et al. are both related to the use of2,5-diaryltetrahydrofurans and their analogs as PAF antagonists. Grahamet al., in 197th Amer. Chem. Soc. National Meeting Abstracts, 1989,MEDI, 25, 20, Corey, et al. in Tet. Lett., Vol. 29, 2899-2902 (1988),and U.S. Pat. No. 4,656,190 to Shen et al. respectively show that1,3-diarylcyclopentanes, 2,4-diaryldioxolanes, and indene derivativesare also potent PAF receptor antagonists.

Leukotrienes, lke PAF, are potent lipid mediators of a variety oftopical and systemic diseases and disorders. 5-lipoxygenase catalyzesthe conversion of arachidonic acid to leukotriene A4 which is theprecursor of leukotrienes B4 and C4. Leukotrienes B4 and C4 areoxygenated metabolites that contribute to the pathogenesis of suchinflammatory disorders as arthritis, asthma, psoriasis, and thromboticdisease. Leukotrienes are released concomitantly from leukocytes withPAF from a common phospholipid precursor upon cellular activation andact synergistically with PAF in many biological models. It has beendemonstrated that a physical combination of a PAF antagonist and aleukotriene inhibitor is significantly more effective than either agentalone in treating asthma in an animal model (see, O'Donnell et al. inTherapeutic Approaches to inflammatory Diseases, Lewis et al., Elsevier,New York, 1989, pp.169-193).

Shen et al., in PAF and Related Lipid Mediators, Plenum Pub., New York,164 (1987) and Page et al., in Trends in Pharmacol. Sci. 10, 1 (1989),pointed out that single compounds which posess the dual inhibitorycapability of PAF and leukotriene inhibition would have greaterantiinflammatory activities than a physical combination of a PAF and aleukotriene inhibitor. Moreover, the chemical combination of PAF and5-lipoxygenase inhibitory activities in one molecule has advantages overdrug combinations in terms of optimal pharmacokinetics, clinicalapplications and developmental costs. However, few compounds are knownwhich posess this dual inhibitory activity. Shen et al., in PAF andRelated Lipid Mediators, Plenum Pub: New York, 153-190 (1987), reportedthat a tetrahydrothiophene analog of lignan, L-653,150, is both a potentPAF antagonists and a moderate inhibitor of 5-lipoxygenase. EuropeanPat. No. Application 0,365,089 to Biftu, filed Oct. 13, 1989, is alsodirected the use of tetrahydrothiophene analoqs as leukotrieneinhibitors and specific PAF antagonists.

Because of the large number of diseases and disorders which are mediatedby leukotrienes and PAF, synthesis of new compounds which posessleukotriene or PAF inhibitory activity, and preferably compounds whichpossess both inhibitory activities, as well as the identification ofexisting compounds which possess either or both inhibitory activities,will provide a great benefit to society in the treatment of thosediseases and disorders.

SUMMARY OF THE INVENTION

It is therefore an object of this invention to provide neolignanderivatives which both act as PAF antagonists and inhibit biosyntheticproduction of leukotrienes via the 5-lipoxygenase pathway.

It is another object of this invention to provide novel2,4-diaryl-1,3-dithiolanes as a new class of potent PAF receptorantagonists which also inhibit 5-lipoxygenase.

It is another object of this invention to provide a method of using2,4-diaryl-1,3-dithiolanes as PAF antagonists and 5-lipoxygenaseinhibitors.

It is another object of this invention to provide stereoselectiveprocesses for the preparation of optical isomers of2,4-diaryl-1,3-dithiolanes.

It is yet another object of this invention to provide a method of usingfutoenone and futoenone derivatives as dual acting PAF antagonists and5-lipoxygenase inhibitors.

It is yet another object of this invention to provide novel futoenonederivatives as potent PAF receptor antagonists which also inhibit5-lipoxygenase.

It is a further object of this invention to provide a method of treatingPAF and leukotriene mediated diseases by using neolignan derivativessuch as 2,4-diaryl-1,3-dithiolanes and futoenone derivatives as dualacting PAF antagonists and 5-lipoxygenase inhibitors.

According to the invention, many new 2,4-diaryl-1,3-dithiolane compoundsand futoenone derivative compounds have been synthesized. Many of thecompounds have been examined in vitro, and have been shown to possessboth PAF and 5-lipoxygenase inhibition activity.

The compounds of the present invention may be employed aspharmaceuticals which include the compound and an acceptablepharmaceutical carrier. Such pharmaceutical compositions may beadministered orally, topically (eg., as an ointment or by means of atransdermal patch), parentally, intranasally (eg., by inhalation spray),or rectally.

The term parenteral as used herein includes subcutaneous injections,intravenous, intramuscular, intrasternal injection or infusiontechniques. In addition to the treatment of warm-blooded animals such asmice, rats, horses, cattle, sheep, dogs, cats, etc., the compounds ofthe invention are effective in the treatment of humans.

The pharmaceutical compositions containing the active ingredient may bein a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, or syrups or elixirs. Compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharamceutical compositions and suchcompositions may contain one or more agents selected from the groupconsisting of sweetening agents, flavoring agents, coloring agents andpreserving agents in order to provide pharamceutically elegant andpalatable preparations. Tablets contain the active ingredient inadmixture with non-toxic pharamceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients may be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents, for example, corn starch, or alginic acid;binding agents, for example starch, gelatin or acacia, and lubricatingagents, for example magnesium stearate, stearic acid or talc. Thetablets may be uncoated or they may be coated by known techniques todelay disintegration and absorption in the gastrointestinal tract andthereby provide a sustained action over a longer period. For example, atime delay material such as glyceryl monostearate or glyceryl distearatemay be employed. They may also be coated by the techniques described inthe U.S. Pat. Nos. 4,256,108; 4,166,452; and 4,265,874 to form osmotictherapeutic tablets for control release.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, clacium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an anti-oxidant such asascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharamceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent, for example as a solution in 1,3-butane diol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds may also be administered in the form of suppositories forrectal administration of the drug. These compositions can be prepared bymixing the drug with a suitable non-irritating excipient which is solidat ordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Such materials arecocoa butter and polyethylene glycols.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compounds are employed.

Dosage levels of the order of from about 0.01 mg to about 150 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.7 mg to about 10 gms. per patientper day, for patients having an average body weight of 70 kg). Forexample, inflammation may be effectively treated by the administrationof from about 0.015 to about 50 mg of the compound per kilogram of bodyweight per day (about 1.0 mg to about 3.5 gms per patient per day).Preferably a dosage of from about 3 mg to about 20 mg per kilogram ofbody weight per day may produce good results (about 20 mg to about 1.5gm per patient per day).

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, aformulation intended for the oral administration to humans may containfrom 0.5 mg to 5 gm of active agent compounded with an appropriate andconvenient amount of carrier material which may vary from about 5 toabout 95 percent of the total composition. Dosage unit forms willgenerally contain between from about 1 mg to about 500 mg of an activeingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination and the severity ofthe particular disease undergoing therapy.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, aspects and advantages will be betterunderstood from the following detailed description of the preferredembodiments of the invention with reference to the drawings, in which:

FIG. 1 is a schematic drawing showing a synthetic pathway for producing2,4-diaryl-1,3-dithiolane compounds;

FIG. 2 is a table showing the substituent groups of many2,4-diaryl-1,3-dithiolane compounds which may be produced according toFIG. 1 and the PAF and 5-lipoxygenase antagonist activities observed forseveral of the compounds;

FIG. 3 is a schematic drawing showing a synthetic pathway for producingthe oxathiolane analog of the diaryltetrahydrofuran L-652,731;

FIG. 4 is a schematic drawing showing a synthetic pathway for producinga single enantiomer of a 2,4-diaryl-1,3-dithiolane compound;

FIGS. 5a and 5b are chemical structures of dimeric2,4-diaryl-1,3-dithiolane compounds;

FIGS. 6a and 6b are tables which respectively show the chemicalsubstituents of the dimeric compounds shown in FIGS. 5a and 5b as wellas data on PAF antagonistic activity;

FIG. 7 is a schematic drawing showing the extraction of futoenone andother compounds from Piper fotukadsura;

FIGS. 8a and 8b are chemical structures of futoenone and a futoenonederivative, respectively, showing the numbering scheme used to identifythe novel compounds of this invention;

FIGS. 9-13 are schematic drawings showing the synthesis of futoenonederivative compounds;

FIGS. 14a and 14b are respectively a chemical structure of a substitutedfutoenone compound and a table showing the PAF antagonist activity ofparticular futoenone derivative compounds;

FIGS. 15a and 15b are respectively a chemical structure of a substitutedfutoenone derivative compound and a table showing the PAF antagonistactivity of particular futoenone derivative compounds;

FIGS. 16a and 16b are respectively a chemical structure of a substitutedfutoenone derivative compound and a table showing the 5-lipoxygenaseinhibitory activity of particular futoenone derivative compounds; and

FIGS. 17 and 18 are schematic drawings showing a synthetic pathway forproducing futoenone and futoenone derivative compounds.

FIG. 19 is a schematic drawing showing the general synthetic approachfor producing 2,4-diaryl-1,3-dithiolane compounds.

FIG. 20 is a schematic drawing showing the synthetic approach forproducing 2,4-diaryl-1,3-dithiolane compounds with an aryl aminofunctionality.

FIG. 21 is a schematic drawing showing the synthetic approach forproducing 2,4-diaryl-1,3-dithiolane compounds with an aryl hydroxyureafunctionality.

FIG. 22 is a schematic drawing showing the synthetic approach forproducing 2,4-diaryl-1,3-dithiolane intermediates with a substitutedaryl niffue, carboxylic acid or methylamino functionalities.

FIG. 23 is a schematic drawing showing the synthetic approach forproducing 2,4-diaryl-1,3-dithiolane intermediates with a pm substitutedaryl carboxylic acid or alkylthio functionalities.

FIG. 24 is a schematic drawing showing the synthetic approach forproducing 2,4-diaryl-1,3-dithiolane intermediates with a M═ substitutedaryl sulfonyl functionalities.

FIG. 25 is a schematic drawing showing the synthetic approach forproducing 2,4-diaryl-1,3-dithiolane compounds with various substitutedaryl amino ethylsulfonyl functionalities.

FIG. 26 is a schematic drawing showing the synthetic approach forproducing 2,4-diaryl-1,3-dithiolane compounds with a quaternary alkylpyridine side chain and its analogs functionalities.

FIGS. 27 & 28 are schematic drawings showing the general syntheticapproach form producing dimeric 2,4-diaryl-1,3-dithiolane compounds withan amide linkage.

FIG. 29 is a schematic drawing producing the general synthetic approachfor producing dimeric 2,4-diaryl-1,3-dithiolane compounds with an aminelinkage.

The invention is also described herein with respect to the followingtables wherein:

Table 1 illustrates inhibition of PAF induced platelet aggregation andinhibition of LTB₄ biosynthesis by dual-acting 2,4-diaryl-1,3-dithiolanehaving the following structural formula: ##STR1## (X, Y, and Z aredescribed in Table 1) and their cis-isomers;

Table 2 illustrates inhibition of PAF induced platelet aggregation andinhibition of LTB₄ biosynthesis by dual-acting2,4-diaryl-1,3-dithiolanes with picolylamine side chain, and having thestructural formula: ##STR2## (R¹, R², and X are described in Table 2),and their cis-isomers;

Table 3 illustrates inhibition of PAF induced platelet aggregation bydimeric 2,4-diaryl-1,3-dithiolanes having the following formula:##STR3## (n is described in Table 3).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

In vitro experiments have been conducted to determine the PAF and5-lipoxygenase inhibitory activity of a variety of synthesized,neolignan derivative compounds. In particular, the novel compounds areeither 2,4-diaryl-1,3-dithiolanes or futoenone derivatives. PAFantagonist activity was determined according to the method of Shen etal., in Methods of Ezymology, Vol. 187, 447-449 (1990), and that articleis herein incorporated by reference. The 5-lipoxygenase inhibitoryactivity was determined according to an assay discussed below.

The following outlines a platelet aggregation assay procedure. Blood isobtained from human volunteers who have not ingested aspirin or steroiddrugs for ten days and is stored with a 3.8% trisodium citrateanticoagulant. Heparin is not used as the anticoagulant since itinterferes with platelet aggregation. Citrated blood is centrifuged at220 g for 10 min. at room temperature to obtain platelet-rich plasma(PRP). The platelet count is determined and is adjusted to 2.5×10⁷platelets/ml. Platelet-poor plasma (PPP) is prepared by centrifuging PRPat 1000 g for 20 min. to pelletize the platelets. PPP is used tocalibrate the aggregometer. Washed platelet suspension (WPS) is preparedfrom PRP by underlayering the latter with Ficoll-Paque (9:2, v/v) andcentrifuging at 750 g for 15 min. at room temperature. The plateletsform a band between the plasma and the separation medium and arecarefully collected and suspended in Tyrode's solution (in mM: NaCl,137; KCl, 2.7; NAHCO₃, 11.9; NaH₂ -PO₄, 0.42; MgCl₂, 1.0; CaCl₂, 1.0;HEPES, 5.0; and dextrose, 1 g/liter, with 0.25% BSA, w/v, pH 7.4).Prostacyclin (PGI₂) (1 ng/ml) can be added to the suspension to preventplatelet activation; however, it should be understood that theinhibitory activity of PGI₂ disappears completely 10 min. from the timeof addition at room temperature. The suspension is then spun at 1000 gfor 10 min. and the pellet is resuspended in Tyrode's buffer forplatelet aggregation. The suspensions are maintained at 37° C. andstirred constantly at 1000 revolutions per min (rpm). A known amount ofPAF, such as 0.11 μM PAF, is added to the suspension three to fiveminutes after the addition of the potential PAF antagonists (thesynthesized compounds). The effect of the PAF antagonist can beexpressed as a percentage inhibition of the observed control maximumplatelet aggregation (the aggregation observed for a suspension to whichonly PAF has been added) or as the concentration of the antagonist whichreduces the maximum response of the platelets by 50% (commonly calledthe IC₅₀ value). To obtain the IC₅₀ value, varying concentrations of apotential antagonist need to be added to the test suspensions with thepercentage inhibition being determined for each concentration of theantagonist, and the IC₅₀ value is obtained from a plot of the percentageinhibition versus concentration of the antagonist.

The 5-lipoxygenase assay can be determined according to the followingprocedure. Human blood is obtained from volunteers who have not takendrugs for the previous ten days. Human polymorphonuclear (PMN)leukocytes and monocytes are isolated according to the procedure bySteven Feinmark, in Methods in Enzymology, Vol. 187, 559 (1990), thisarticle being incorporated herein by reference. Using an adaptedprocedure of McColl et al., J. Chromatography, Vol. 378, 444 (1986),this article being herein incorporated by reference, the isolated PMNand/or monocyte pellets are suspended in Hank's balanced salt solution(HBSS) and cooled in an ice bath. Varying concentrations of potentialantagonists (i.e., the synthesized compounds) are added to tubescontaining the suspension, except for four control tubes. The suspensionand potential 5-lipoxygenase inhibitors are mixed thoroughly.Arachidonic acid is added to two of the controls (0° C.) followedimmediately by quenching with ethyl acetate. Arachidonic acid (10 μl ofa 10 mM solution) is then added to and mixed thoroughly with thesuspension (1 ml) in the remaining tubes followed by the addition of acalcium ionophore A23187 (5 μl of 1 mM solution) to all tubes except the0° C. controls (those already being quenched with ethyl acetate) andincubation of the tubes at 37° C. proceeds for two minutes. The reactionin each tube was quenched and the metabolites extracted by adding ethylacetate (1 ml) to each tube followed by centrifugation of the entiretube at 1000 g for five minutes. This extraction produces two layerswhere the top layer is ethyl acetate that is separated and subsequentlyremoved by drying under a stream of nitrogen. The residues areredissolved in methanol. Leukotriene B₄ (LTB₄) is monitored using anHPLC set to absorb at 280 nm. The retention time for LTB₄ is determinedusing a pure standard, such as that which can be purchased from SigmaChemical. Care should be taken to maintain the samples at lowtemperature prior to injection in the HPLC. The peak areas associatedwith LTB₄ formation are determined (preferably in duplicate andaveraged) for each sample and the percent inhibition for eachconcentration level of inhibitor was calculated according to Equation 1:##EQU1##

Referring now to the drawings and, more particularly to FIG. 1, thenovel 2,4-diaryl-1,3- dithiolanes are synthesized by first converting anarylaldehyde (A) to an epoxide (B) using tert-butylammonium iodide(TBAI), trimethylsulfonium iodide, and sodium hydroxide. The epoxide (B)is then reacted with carbon disulfide, potassium hydroxide and methanolto produce a 4-aryl-1,3-dithiolane-2-thione (C) which is then reducedwith lithium aluminum hydride to produce a 1-aryl-1,2- ethanedithiol(D). The 1-aryl-1,2-ethanedithiol is then reacted with an arylaldehyde(E), which can be the same as the starting reactant, by cyclizing withpyridinium para-toluene sulfonate (PPTS) or camphor sulfonic acid. Thecyclizing reaction produces 2,4- diaryl-1,3-dithiolane compounds (F) ina mixture of 1:1 to 3:1 cis:trans isomers depending on the respectivecatalyst. The cis and trans isomers can be obtained by successiverecrystallizations in methanol, hexane/ethyl acetate, ordichloromethane/hexane.

The following examples describe the synthesis of a number of compoundswhich have been produced and relate particularly to FIG. 1 where theintermediate compounds are identified by numbers 24-43 and the2,4-diaryl-1,3-dithiolane compounds produced are identified by numbers1-21. Details on particular compounds that may also be synthesizedaccording to the scheme of FIG. 1 are also provided; however, it shouldbe understood that compounds within the scope of this invention can besynthesized by routes other than those outlined in the followingexamples and that compounds with different combinations of substituentson the aryl rings are within the scope of this invention, and furtherthat the dithiolane ring can be substituted with moieties other thanhydrogen, e.g., halogens, haloloweralkyls, --CONR² R³ wherein R² and R³independently represent C₁₋₁₀ alkyl and hydrogen, loweralkenyl, --COR²,CH₂ OR², lower alkynyl --CH₂ NR² R³ or --CH₂ SR², in a manner similar tothat described in U.S. Pat. No. 4,539,332 which is herein incorporatedby reference.

EXAMPLE 1 Cis and trans-2,4-bis-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 1)

Step A: Preparation of 1-(3,4,5-trimethoxyphenyl)oxirane (28)

3,4,5-trimethoxybenzaldehyde (24) (9.80g, 50.0 mmole) is dissolved in 20ml CH₂ Cl₂ along with tetrabutylammonium iodide (0.396 g, 1.00 mmole).To this solution is added a cooled 50% NaOH solution (10 g NaOH in 10 mlH₂ O). To this mixture is added trimethysulfonium iodide (10.20 g, 50.0mmole). The reaction is refluxed with vigorous stirring for 15 hours.The reaction is quenched with H₂ O, extracted with CH₂ Cl₂, washed withbrine, dried over MgSO₄ and evaporated to an oil (9.69 g, 84%) whichsolidifies to a white solid after 24 hours in vacuo.

NMR: (CDCl₃) 2.75,dd,1H;3.11,dd,1H;3.81,d,1H;3.82,s,3H;3.85,s,6H;6.50,s,2H M.S. (CI) :211 (100%). Melting Point:54.5°-56° C. C,H Analysis: (theoretical, actual) C (62.85,62.63); H(6.71,6.76).

Step B: Preparation of4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane-2-thione (32)

Powdered potassium hydroxide (2.40 g, 42.85 mmole) is dissolved in 10.0ml methanol and carbon disulfide (3.10 ml, 51.43 mmole) is added at 0°C. under an N₂ atmosphere. The reaction mixture is shaken vigorously and1-(3,4,5-trimethoxyphenyl) oxirane (28) (3.50 g, 16.66 mmole) is added.The reaction is allowed to warm to room temperature at which point thereaction starts to reflux for twenty minutes. Subsequently, the reactionis stirred at room temperature overnight. A yellow precipitate isisolated by suction filtration and is washed with H₂ O and diethyletherto yield 3.82 g (76%).

NMR: (CDCl₃) 3.85,s,3H;3.88,s,6H;3.99,dd,1H;4.17,t,1H;5.57,dd,1H;6.70,s,2H. M.S.: (IBu) 303 (100%). Melting Point:152°-154° C. C,H,S Analysis: (theoretical, actual) C (47.66,47.90); H(4.67,4.70); S (31.80,31.71).

Step C: Preparation of 1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (38)

Lithium aluminum hydride (0.20 g, 5.27 mmole) is added to 15 ml drydiethylether. To this slurry is added4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane-2-thione (32) (1.0 g, 3.31mmole) predissolved in 20 ml dry THF. The reaction is refluxed under anN₂ atmosphere for 12 hours. The reaction is cooled to 0° C. and theexcess hydride destroyed with H₂ O. The reaction mixture is acidifiedwith 10% HCl and immediately extracted with diethyl ether. The organiclayer is washed with H₂ O, dried over MgSO₄, filtered and evaporated toa white solid (9.836 g, 97%). NMR: (DCDl₃)2.34,d,1H;2.95,m,1H;3.09,m,1H; 3.84,s,3H;3.87,s,6H;4.03,m,1H;6.53,s,2H.M.S. (IBu) 261 (100%). Melting Point: 72.5°-73.5° C. C,H,S Analysis:(theoretical, actual) C (50.74,50.85); H (6.19,6.20); S (24.63,24.53).

Step D: Preparation of cis andtrans-2,4-bis-(3,4,5-trimethoxyphenyl)-1,3-dithiolane (new compound 1)

1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (38) (0.56 g, 2.15 mmole),3,4,5-trimethoxybenzaldehyde (24) (0.35 g, 1.78 mmole) and 0.178 g ofpyridinium paratoluene sulfonate are added to 40 ml dry benzene andrefluxed with Dean-Stark removal of the benzene-water azeotrope for 24hours. The benzene is removed in vacuo, and the remaining oilredissolved in ethyl acetate. The organic layer is washed with H₂ O andwas dried over MgSO₄, filtered, and evaporated in vacuo to a white foamwhich is purified by flash column chromatography using 1:1 hexane/ethylacetate as eluent (0.630 g, 81%). The trans isomer is isolated from the1:1 mixture of diastereomers after three recrystallizations frommethanol (25 mg). If the above reaction is performed under reducedpressure (aspirator) at 45° C. for 2.5 hours using camphor sulfonic acidas the catalyst, the product mixture contains a 3:1 cis/trans ratio ofdiastereomers. The cis diastereomer is isolated from this productmixture by recrystallization from either methanol or hexane/ethylacetate.

Trans epimer:

NMR: (CDCl₃): 3.48,dd,1H;3.65,dd,1H;3.84,s,6H;3.88,s,12H;5.06,dd,1H;5.83,s,1H;6.72,s,2H;6.83,s,2H. M.S. (CI): 439(100%) Melting Point: 111° C. C,H,S Analysis: (theoretical, actual) C(57.51,57.57); H (5.97,5.98); S (14.62,14.52).

Cis epimer:

NMR: (CDCl₃): 3.55-3.58,d,2H;3.84-3.87,3s,18H;4.84,t,1H;5.75,s,1H;6.75,s,2H;6.86,s,2H. M.S. (CI): 439 (100%) MeltingPoint: 100°-101° C. C,H,S Analysis: (theoretical, actual) C(57.51,57.40); H (5.97,6.00); S (14.62,14.68).

EXAMPLE 2

2-(3-hydroxy-4,5-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane (compound 2) (M.S. (CI):425,195 (100%);

2-(3-benzoyloxy-4,5-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 3) (M.S. (CI): 529,195 (100%);

2-(3-methoxymethoxy-4,5-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 4) (M.S. (CI) :469,195 (100%);

Trans2-(4-hydroxy-3,5-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 5) (C.H.S. Analysis (theoretical, actual) C (56.58,56.68), H(5.70,5.71), S (15.10,15.04);

Trans2-(4-hydroxy-3-nitro-5-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 6) (C.H.S. Analysis (theoretical, actual) C (51.92,52.03), H(4.82,4.86), S (14.59,14.51);

Trans2-(4-hydroxy-3-iodo-5-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 7) (C.H.S Analysis (theoretical, actual) C (43.85,43.93), H(4.07,4.09), S (12.32,12.42));

Trans2-(4,5-dimethoxy-3-iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 8) (M.S. (CI):535,195 (100%));

Trans2-(4-hydroxy-3,5-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 9) (C.H.S. Analysis (theoretical, actual) C (61.20,61.08), H(6.16,6.20), S(16.34,16.44)); and

Trans2-(4-hydroxy-3,5-dimethylphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 10) (C.H.S. Analysis (theoretical, actual) C(65.51,65.50),H(7.61,7.64), S(13.45,13.55)) are prepared following substantially thesame procedures as described in Example 1; however, the constituents ofthe arylaldehyde (E) are different for each of the new compounds 2-10.Specifically, the 2,4-diaryl-1,3-dithiolanes (F) have the followingconstituents:

    ______________________________________                                        Compound    A            B         C                                          ______________________________________                                        2           OH           OCH.sub.3 OCH.sub.3                                  3           OCOPh        OCH.sub.3 OCH.sub.3                                  4           OCH.sub.3 OCH.sub.3                                                                        OCH.sub.3 OCH.sub.3                                  5           OCH.sub.3    OH        OCH.sub.3                                  6           NO.sub.2     OH        OCH.sub.3                                  7           I            OH        OCH.sub.3                                  8           I            OCH.sub.3 OCH.sub.3                                  9           CH.sub.3     OH        CH.sub.3                                   10          t-butyl      OH        t-butyl                                    ______________________________________                                    

The aryladehydes (E) utilized are either commercially available orsynthesizable by well known procedures.

EXAMPLE 3

Trans 2,4-bis-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-dithiolane (compound11) and Trans2-(3,4,5-trimethoxyphenyl)-4-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-dithiolane(compound 12) are prepared according to the scheme shown in FIG. 1.

Step A: Preparation of 1-(3,5-dimethoxy-4-methoxymethoxyphenyl) oxirane(29)

3,5-dimethoxy-4-methoxymethoxybenzaldehyde (25) [55211-66-0] (10.85 g,48.0 mmole) is dissolved in 20 ml CH₂ Cl₂ along with tetrabutylammoniumiodide (0.40 g, 1.00 mmole). To this solution is added a cooled 50% NaOHsolution (10 g NaOH in 10 ml H₂ O). To this mixture is addedtrimethylsulfonium iodide (10.77 g, 52.81 mmole). The reaction isrefluxed with vigorous stirring for 48 hours. The reaction is quenchedwith H₂ O, extracted with CH₂ Cl₂, washed with brine, dried over MgSO₄and evaporated to an oil (9.69 g, 84%). The oil can be crystallized fromhexane/ethyl acetate. NMR: (CDCl₃) 2.70,m,1H;3.10,m,1H;3.60,s,3H;3.90,s,6H;5.09,s,2H;6.50,s,2H.

Step B: Preparation of4-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1,3-dithiolane-2-thione (33)

Powdered potassium hydroxide (1.75 g, 31.25 mmole) is dissolved in 3.0ml methanol and carbon disulfide (2.85 g, 37.5 mmole) was added at 0° C.The reaction mixture is shaken vigorously and3,5-dimethoxy-4-methoxymethoxyphenyloxirane (29) (3.0 g, 12.5 mmole) isadded. The reaction is allowed to warm to room temperature at whichpoint the reaction starts to reflux. The reaction is stirred at roomtemperature for 24 hours, and is quenched with ethyl acetate and 10%NaOH. The organic layer is washed with 3×40 ml 10% NaOH, 1×30 ml H₂ O,2×30 ml ss NaCl, dried over MgSO₄, and evaporated in vacuo to a yellowoil which is purified by flash column chromatography using 2:1hexane/ethyl acetate. The product was recrystallized from hexane/ethylacetate (4.52 g, 63% yield).

NMR: (CDCl₃) 3.59,s,3H;3.86,s,6H;3.98,dd,1H;4.16,dd,1H;5.12,s,2H;5.58,dd,1H;6.70,s,2H. M.S.: (IBu) 333 (100%)Melting Point: 97.5°-99° C. C,H,S Analysis: (theoretical, actual) C(46.97,47.06); H (4.85,4.88); s (28.93,28.83).

Step B2: Preparation of4-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-dithiolane-2-thione (34)

Powdered potassium hydroxide (3.50 g, 62.50 mmole) is dissolved in 6.0ml methanol and carbon disulfide (5.70 g, 75.0 mmole) is added at 0° C.The reaction mixture is shaken vigorously and3,5-dimethoxy-4-methoxymethoxyphenyloxirane (29) (6.0 g, 25.0 mmole) isadded. The reaction is allowed to warm to room temperature at whichpoint the reaction starts to reflux. The reaction is stirred at roomtemperature for 24 hours, and is quenched with ethyl acetate and 10%NaOH. The organic layer is washed with 3×40 ml 10% NaOH, 1×30 ml H₂ O,and 2×30 ml ss NaCI. The ethyl acetate is reduced to 10 ml and 30 mlmethanol along with 10 ml 5.0M methanolic HCl. The reaction is stirredfor three hours, quenched with 100 ml H₂ O, extracted with ethylacetate, dried over MgSO₄, and evaporated in vacuo to a yellow oil whichis purified by flash column chromatography using 2:1 hexane/ethylacetate. The product is recrystallized from hexane/ethyl acetate (4.52g, 63% yield).

NMR: (CDCl₃) 3.91,s,6H;3.97,t,1H;4.16,t,1H;5.58,dd,1H;5.60,s,1H;6.71,s,2H. M.S.: (CI) 289 (100%). MeltingPoint: 96°-97° C. C,H,S Analysis: (theoretical, actual) C (45.81,45.91);H (4.19,4.22); S(33.35,33.25).

Step C1: Preparation of1-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1,2-ethanedithiol (39).

Lithium aluminum hydride (0.622 g, 16.38 mmole) is added to 60 ml drydiethyl ether. To this slurry is added dropwise4-(3,5-dimethoxy-4-methoxymethoxyphenyl)-1,3-dithiolane-2-thione (33)(3.40 g, 10.24 mmole) predissolved in 35 ml dry THF. The reaction isstirred under an N₂ atmosphere until the solution becomes colorless (4hours). The reaction is cooled to 0° C. and the excess hydride destroyedwith H₂ O. The reaction mixture is acidified with 10% HCl andimmediately extracted with diethyl ether. The organic layer is washedwith H₂ O, dried over MgSO₄, filtered and evaporated to a white solid(2.47 g, 84%). NMR: (CDCl₃) 2.33,d,1H;2.90,m,1H;3.10,m,1H;3.59,s,3H;3.85,s,6H;4.03,m,1H;5.10,s,2H;6.53,s,2H Melting Point: 84°-85°C. C,H,S analysis: (theoretical, actual) C (49.63,49.52); H (6.25,6.28);S (22.08,22.16).

Step C2: Preparation of1-(3,5-dimethoxy-4-hydroxyphenyl)-1,2-ethanedithiol (40)

Lithium aluminum hydride (0.553 g, 14.58 mmole) is added to 10 ml drydiethyl ether and 10 ml dry THF. To this slurry is added dropwise4-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-dithiolane-2-thione (34) (2.00 g,6.94 mmole) predissolved in 40 ml dry THF. The reaction is stirred undera nitrogen (N₂) atmosphere until the solution becomes colorless (1hour). The reaction is cooled to 0° C. and the excess hydride destroyedwith H₂ O. The reaction mixture is acidified with 10% HCl andimmediately extracted with diethyl ether. The organic layer was washedwith H₂ O, dried over MgSO₄, filtered and evaporated to a white solid(1.64 g, 96%).

NMR: (CDCl₃) 2.33,d,1H;2.93,m,1H;3.10,m,1H;3.90,s,9M;4.03,m,1H;5.50,s,1H;6.54,s,2H. M.S. (CI): 247,213 (100%)

Step D1: Preparation oftrans-2,4-bis-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-dithiolane (compound11)

1-(3,5-dimethoxy-4-hydroxyphenyl-1,2-ethanedithiol (40) (2.46 g, 10.0mmole), 3,5-dimethoxy-4-hydroxybenzaldehyde (indicated as arylaldehyde Ein FIG. 1) (1.32 g, 7.20 mmole) and 1.00 g of pyridinium paratoluenesulfonate are added to 50 ml dry benzene and refluxed with Dean-Starkremoval of the benzene-water azeotrope overnight. The benzene is removedin vacuo, and the remaining oil redissolved in dichloromethane. Theorganic layer is washed with 10% NaHCO₃ and H₂ O. The organic layer isdried over MgSO₄, filtered, and evaporated in vacuo to a white solidwhich is recrystallized from methanol (2.510 g, 85%). The trans isomer(0.683 g) is isolated by recrystallization from methanol. NMR: (CDCl₃)3.45,dd,1H;3.61,dd,1H;3.91,s,6H;3.92,s,6H;5.07,dd,1H;5.50,d,2H;5.83,s,1H; 6.73,s,2H;6.84,s,2H.M.S.: (CI) 411 (100%). Melting Point: 169°-170° C. C,H,S Analysis:(theoretical, actual) C (55.59,55.58); H (5.40,5.44); S (15.62,15.56).

Step D2: Preparation of2-(3,4,5-trimethoxyphenyl)-4-(3,5-dimethoxy-4-hydroxyphenyl)-1,3-dithiolane(compound 12)

1-(3,5-dimethoxy-4-hydroxyphenyl)-1,2-ethanedithiol (40) (2.10 g, 8.54mmole), 3,4,5-trimethoxybenzaldehyde (24) (1.28 g, 6.57 mmole) and 0.857g of pyridinium paratoluene sulfonate are added to 60 ml dry benzene andrefluxed with Dean-Stark removal of the benzene-water azeotropeovernight. The benzene is removed in vacuo, and the remaining oil isextracted into 10% NaOH which was washed with diethylether. The basiclayer is reacidified with 10% HCl and the desired product is extractedinto ethyl acetate. The organic layer is dried over MgSO₄, filtered, andevaporated in vacuo to an oil which is purified by flash columnchromatography with 2:1 hex/ethyl acetate as eluent. The product mixturecontains a 1.0/1.2 cis/trans ratio after the first recrystallization(1.287 g, 59%). The trans isomer is isolated after six additionalrecrystallizations from methanol.

NMR: (CDCl₃) 3.50,dd,1H;3.61,dd,1H;3.84.,s,3H;3.89,s,6H;3.91,s,6H;5.06,dd,1H;5.51,s,1H;5.82,s,1H; 6.73,s,2H;6.83,s,2H.M.S.: (CI) 425 (100%) 212. Melting Point: 129°-130° C. C,S Analysis:(theoretical, actual) C (56.58,56.52); H (5.70,5.74).

EXAMPLE 4 Trans-2-(3,5-dithiomethyl-4-hydroxyphenyl)-1,3-dithiolane(Compound 13A (FIGS. 1 and 2))

3,5-dithiomethyl-4-hydroxybenzaldehyde (26) (0.822 g, 3.84 mole), whichis described in European Pat. No. Application 0,319,947, Jul. 12, 1988,to the Green Cross Corporation and which is herein incorporated byreference, 1-(3,4,5-trimethoxyphenyl)-1,2-ethane dithiol (38) (1.20 g,4.61 mmole) and 0.460 g of pyridinium paratoluene sulfonate are added to45 ml dry benzene and refluxed with Dean-Stark removal of thebenzene-water azeotrope overnight. The benzene is removed in vacuo, andthe remaining oil redissolved in ethyl acetate. The organic layer iswashed with 10% NaHCO₃ and H₂ O. The organic layer is dried over MgSO₄,filtered, and evaporated in vacuo to an oil which is purified by flashcolumn chromatography with 2:1 hex/ethyl acetate as eluent. 621 mg ofproduct crystallize out of the column fractions as a 1.4/1.0 trans/cismixture. (Total yield=1.428 g, 82%). The trans epimer is isolated as a6/1 trans/cis mixture.

Trans epimer: NMR: (CDCl₃) 2.42,s,6H;3.47,dd,2H;3.65,dd,2H;3.84,s,3H;3.88,s,6H;5.06,dd,1H;5.79,s,1H; 6.72,s,2H;7.08,s,1H;7.48,s,2H. M.S. (CI): 457 (100%) Melting Point: 144°-145°C. C,H,S Analysis: (theoretical, actual) C (52.60,52.59); H (5.30,5.34);S (28.08,27.98).

2,4-bis-(3,5-dithiomethyl-4-hydroxyphenyl)-1,3-dithiolane (compound 13bin FIG. 2), 2,4-bis-(3,5-dithiomethyl-4-methoxyphenyl)-1,3-dithiolane(compound 13c in FIG. 2), and2-(3,5-dithiomethyl-4-methoxyphenyl)-4-(3,5-dithiomethyl-4-hydroxyphenyl)-1,3-dithiolane(compound 13e of FIG. 2) have not yet been prepared but could beprepared as described above using3,5-dithiomethyl-4-methoxymethoxybenzaldehyde (27) as the startingmaterial. Similarly,2-(3,5-dithiomethyl-4-hydroxyphenyl)-4-(3,5-dithiomethyl-4-methoxyphenyl)-1,3-dithiolane(compound 13d of FIG. 2) has not yet been prepared but could be preparedas described above using 3,5-dithiomethyl-4-hydroxybenzaldehyde as astarting material.

EXAMPLE 5Trans-2-(3-(2-hydroxyethylsufonyl)-5-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 14)

Step A: Preparation of3-(2-hydroxyethylthio)-5-methoxy-4-propoxybenzaldehyde

5-iodo-3-methoxy-4-propoxybenzaldehyde (6.166 g, 19.27 mmole), copperpowder (10.41 g, 163.78 mmole), and 45 ml dimethylformamide (DMF) arestirred vigorously under a N₂ atmosphere at 140° C. for 3 hours. To thisslurry is added 2-hydroxy ethyldisulfide (4.75 g, 30.8 mmole)predissolved in 10 ml DMF. The reaction is stirred at 140° C. overnight.The copper is removed by suction filtration through celite, and iswashed thoroughly with ethyl acetate. The filtrate is concentrated to anoil in vacuo and then redissolved in dichloromethane. The organic layeris washed with H₂ O, dried over magnesium sulfate, and concentrated toan oil in vacuo which is purified by flash column chromatography using1:1 hex/ethyl acetate as eluent to yield a light yellow oil (4.00 g,77%).

NMR: (CDCl₃) 1.06,t,3H;1.85,m,2H;3.13,t,2H;3.74,t,2H;3.91,s,3H;4.08,t,2H;7.31,d,1H;7.46,d,1H;9.86,s,1H. M.S. (CI): 271(100%).

Step B: Preparation of2-(3-(2-hydroxyethylthio)-5-methoxy-4-propoxyphenyl)-1,3-dioxalane

3-(2-hydroxyethylthio-3-methoxy-4-propoxybenzaldehyde (0.738 g, 2.73mmole), ethylene glycol (0.678 g, 10.92 mmole), PPTS (0.274 g, 1.09mmole) and 40 ml dry benzene are refluxed with Dean-Stark removal of thebenzene-water azeotrope for five hours. The benzene is removed in vacuoand the remaining oil redissolved in CH₂ Cl₂ which is washed with 10%NaHCO₃, H₂ O and dried over sodium sulfate. The solvent is removed invacuo and the oil purified by flash column chromatography using 2:1hex/ethyl acetate as eluent to yield a light tan oil (0.616 g, 71%).NMR: (CDCl₃) 1.03,t,3H;1.84,m,2H;3.05,t,2H;3.66,t,2H;3.85,s,3H;3.95,t,2H;4.07,m,4H;5.71,s,1H; 6.93,d,1H;7.08,d,1H.

Step C: Preparation of3-(2-hydroxyethylsulfonyl)-5-methoxy-4-propoxybenzaldehyde

2-(3-(2-hydroxyethylthio)-5-methoxy-4-propoxyphenyl)-1,3-dioxalane (2.11g, 6.70 mole) is dissolved in 15 ml CH₂ Cl₂ and is cooled to 0° C. underan N₂ atmosphere. To this solution is slowly added 80%metachloroperoxybenzoic acid (MCPBA) (3.32 g, 15.41 mmole) along with anadditional 10 ml CH₂ Cl₂. The reaction is allowed to warm to roomtemperature over a six hour period. The m-chlorobenzoic acid precipitateis removed by suction filtration and the filtrate is washed with 10%NaHCO₃ and H₂ O. The organic layer is then added to 20 ml 10% HCl andthe mixture is stirred vigorously overnight. The organic layer isseparated, dried over MgSO₄, and evaporated to an impure white solidwhich is purified by flash column chromatography using 2:1 hexane/ethylacetate as eluent no yield a white solid (1.20 g, 60%).

NMR: (CDCl₃)1.03,t,3H;1.88,m,2H;2.70,brs,1H;3.65,t,2H;3.96,s,3H;3.98,t,2H;4.24,t,2H;7.68,d,1H;7.80,d,1H;9.93,s,1H. M.S. (IBu) 302 (100%). Melting Point: 111°-112° C. C,H,SAnalysis: (theoretical, actual) C (51.64,51.67); H (6.00,5.99); S(10.60,10.52).

Step D: Preparation of2-(3-(2-hydroxyethylsulfonyl)-5-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(Compound 14 on FIG. 2)

1-(3-(2-hydroxyethylsulfonyl)-5-methoxy-4-propoxybenzaldehyde (0.409 g,1.35 mmole), 1-(3,4,5-trimethoxyphenyl)-1,2-ethane dithiol (0.50 g, 2.03mmole) and 0.203 g of pyridinium paratoluene sulfonate is added to 45 mldry benzene and refluxed with Dean-Stark removal of the benzene-waterazeotrope overnight. The benzene is removed in vacuo, and the remainingoil redissolved in dichloromethane. The organic layer is washed with 10%NaHCO₃ and H₂ O. The organic layer is dried over MgSO₄, filtered, andevaporated in vacuo to an oil which is purified by flash columnchromatography with 2:1 hex/ethyl acetate as eluent. The product mixture(white foam) contains a 1.0/1.2 cis/trans ratio (0.370 g, 52%).Trans/cis epimers:

NMR: (CDCl₃) 1.04,t,6H;1.87,m,4H;3.45-3.60,m, 4H;3.64,t,4H;3.92,s,12H;3.95,s,6H;3.97,t,4H;4.12,t,4H;4.88,dd,1H;5.07,dd,1H;5.53,s,2H;5.74,s,1H;5.82,s,1H;6.73,s,2H;6.76,s,2H;7.41,d,1H;7.43,d,1H;7.71,d,1H; 7.80,d,1H. M.S.(IBu): 544 (100%) C,H,S Analysis: (theoretical, actual) C (52.92,52.72);H (5.92,5.89); S (17.66,17.53).

EXAMPLE 7

Following substantially the same procedure as described in Example 6,2-(3-methylsulfonyl-5-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 15 on FIG. 2) (C.H.S. Analysis (theoretical,actual) C(53.67,53.75); H (5.88,5.93); S(18.69,18.75)),2-(4,5-dimethoxy-3-(2-hydroxyethylsulfonyl)phenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 16 on FIG. 2) (M.S. (IBu) 517,263 (100%)), and2-(3-(2-(p-nitrobenzoate)ethylsulfonyl)-5-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 17 on FIG. 2) (C.H.S. Analysis (theoretical, actual) C(53.67,53.75); H (5.08,5.10); S (13.86,13.78)) are prepared.

EXAMPLE 8Trans-2-(3,5-dimethoxy-4-(2-hydroxyethoxy))-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 18 of FIG. 2)

Step A: Preparation of 3,5-dimethoxy-4-(2-hydroxyethoxy) benzaldehyde

Syringaldehyde (1.0 g, 5.49 mmole), 2-iodo-1-ethanol (1.90 g, 10.98mmole) and potassium carbonate (1.90 g, 13.77 mmole) are added to 15 mldry DMF and stirred for 24 hours at 80° C. under an argon atmosphere.The reaction mixture is added to 100 ml H₂ O and acidified with 10% HCl.The product is extracted into CHCl₃, dried over MgSO₄, and concentratedto an oil in vacuo. The remaining oil is purified by flash columnchromatography using 1:1 hex/ethyl acetate as eluent (1.009 g, 81%).

NMR: (CDCl₃) 3.23,t,1H;3.73,m,2H;3.93,s,6H;4.20,t,2H;7.13,s,2H;9.87,s,1H M.S. (CI): 227 (100%).

Step B: Preparation oftrans-2-(3,5-dimethoxy-4-(2-hydroxyethoxy))-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane

3,5-dimethoxy-4-(2-hydroxyethoxy) benzaldehyde (2.14 g, 9.47 mmole),1-(3,4,5-trimethoxyphenyl)-1,2-ethane dithiol (2.54 g, 9.77 mmole) and1.00 g of pyridinium paratoluene sulfonate is added to 75 ml dry benzeneand refluxed with Dean-Stark removal of the benzene-water azeotrope for24 hours. The benzene is removed in vacuo, and the remaining oilredissolved in ethyl acetate. The organic layer is washed with 10% HCland H₂ O. The organic layer is dried over MgSO₄, filtered, andevaporated in vacuo to an oil which is purified by flash columnchromatography with 1:2 hex/ethyl acetate as eluent. The product mixture(white foam) triturates to a solid in diethylether (3.10 g, 70%). Thetrans isomer is isolated after three recrystallizations from CH₂ Cl₂/hexane (1.00 g).

NMR: (CDCl₃) 3.40,t,1H;3.48,dd,1H;3.64,dd;3.72,m,2H;3.84,s,3H;3.88,s,6H;3.90,s,6H;4.13,t,2H;5.06,dd,1H;5.83,s,1H;6.72,s,2H;6.85,s,2H.M.S. (CI): 469 (100%). Melting point: 121°-122° C.

EXAMPLE 9

Following substantially the same procedure outlined in Example 8,2-(3,5-dimethoxy-4-(3-bromopropoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 19) (M.S. (CI) 547,195 (100%)),2-(4,5-dimethoxy-3-(2-hydoxyethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 20) (M.S. (CI) 469, 195, 84 (100%), and2-(4,5-dimethoxy-3-(3-hydoxypropoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 21) (M.S. (CI) 483, 195, 84 (100%)) are prepared.

Referring now to both FIGS. 1 and 2, many 2,4-diaryl-1,3-dithiolanecompounds have been synthesized according to the scheme shown in FIG. 1and discussed in Examples 1-9 and many other compounds are readilysynthesizable via the same scheme. Several of these compounds have beentested for their antagonist activity for PAF induced plateletaggregation and for their inhibition of the production of leukotrienesvia the 5-lipoxygenase pathway in PMN leukocytes and monocytes accordingto the procedures described above. FIG. 2 shows that smallconcentrations of these compounds can inhibit both PAF plateletaggregation and the 5-lipoxygenase pathway; therefore, these compoundswould be beneficial for the treatment of the large number of diseasesand disorders which are mediated by leukotrienes and PAF.

FIG. 3 shows the synthesis route for the preparation of the oxathiolane(F') analog of the diaryltetrahydrofuran L-652,731. This compound wassynthesized for the purpose of comparing its antagonistic activity tocompound 1 (FIGS. 1 and 2) of the present invention, which is thedithiolane (F) analog of diaryltetrahydrofuran L-652,731.3,4,5-trimethoxystyrene (B') is formed by a Wittig reaction from3,4,5-trimethoxybenzaldehyde (A') and methyltriphenylphosphoniumbromide.The styrene (B') was converted to the bromohydrin (C') using NBS and wetDMSO. The bromohydrin (C') was converted thiouronium salt (D'), usingthiourea and subsequently hydrolyzed using sodium hydroxide to producehydroxythiol (E'). Similar to FIG. 1, the hydroxythiol (E') was reactedin an acid catalyzed thioketal cyclization with 3,4,5-trimethoxybenzaldehyde to produce the oxathiolane (F'). Of particularsignificance, the oxathiolane (F') was found to be a much weakerantagonist of PAF-induced platelet aggregation than the correspondingdithiolane compound which had an IC₅₀ value of less than 1 μM.

FIG. 4 shows a procedure for preparing R,S-enantiomer of compound 7(FIGS. 1 and 2 show the preparation of a racemic mixture of compound 7,specifically,(R,S)-Trans-2-(4-hydroxy-5-iodo-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane.The importance of testing potential drugs in both their racemic andenantiomeric form has received increasing attention in the scientificcommunity. Jamali et al., in J. Pharm. Sci., 78. 695 (1989),demonstrated than the pharmokinetic and pharmodynamic interactions of aracemic drug is more complex than the sum of the contributions of theindividual enantiomers. In a racemic mixture, the inactive enantiomermay agonize or antagonize pharmocologic and/or toxicologic activities.Thus, it may be preferable to use a single enantiomer for therapeuticapplications. Example 10 describes the synthetic process shown in FIG.4.

EXAMPLE 10 (R,S)-Trans-2-(4-hydroxy-5-iodo-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane

Step A: Preparation of 2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone (A")

Freshly pulverized copper bromide (15.00 g, 67.82 mole) is refluxed in50 ml chloroform 3,4,5-trimethoxyacetophenone (7.50 g, 35.67 mmole)predissolved in 50 ml chloroform is added and the reaction refluxedovernight. The copper bromide is removed by filtration through celiteand the solvent removed in vacuo to leave a dark yellow-brown oil.Crystallization of this oil has been unsuccessful and the product ispurified by flash column chromatography using 2:1 hex/ethyl acetate aseluent (7.90 g, 77%). 1-(3,4,5-trimethoxyphenyl)-2,2-dibromoethanone isisolated as a minor side product.

NMR: (CDCl₃) 3.93,s,6H;3.94,s,3H;4.41,s,2H;7.24,s,2H Melting Point:67°-68° C.

Step B: Preparation of (R)-2-bromo-1-(3,4,5-trimethoxyphenyl) ethanol(B")

2-bromo-1-(3,4,5-trimethoxyphenyl)ethanone (A1) (7.90 g, 27.33 mmole) isdissolved in 50 ml dry THF and is cooled to -20° C. under an N₂atmosphere. To this solution is added (-)-B-chlorodiisopinocampheylborane (14.90 g, 46.50 mmole) predissolved in 50 ml dry THF. Thereaction is stirred at -20° C. for 6 hours. THF is removed in vacuo andthe remaining oil redissolved in diethyl ether. To this solution isadded diethanolamine (7.33 g, 69.75 mmole) and is stirred overnight. Thesolid is removed by filtration and the filtrate washed with H₂ O, driedover MgSO₄, filtered and evaporated to an oil which is purified by flashcolumn chromatography using 2:1 hex/ethyl acetate as eluent in order toremove the pinene side product. (6.268 g, 79%: [α]²¹ D=-28.0^(s) 1%CHCl₃). After one recrystallization from ether/hexane, the rotationincreased to [α]²¹ D=30.40^(s) 1% CHCl₃ (5.50 g, 69%).

NMR: (CDCl₃) 2.71,d,2H;3.51,dd,1H;3.62,dd,1H;3.82,s,3H;3.86,s,6H;4.85,ddd,1H;6.60,s,2H. M.S.: (IBu) 292,290,273.Melting Point: 79°-80° C. C,H,Br Analysis: (theoretical, actual) C(45.38,45.44), H (5.19,5.22), Br (27.45,27.36).

The Mosher ester derivation of (R)-2-bromo-1-(3,4,5-trimethoxyphenyl)ethanol (C") was prepared as follows to determine the optical purity.(R)-2-bromo-1-(3,4,5-trimethoxyphenyl) ethanol (B") (0.025 g, 0.086mmole), (R) (+)-α-methoxy-α-(trifluoromethyl) phenylacetic acid chloride(0.024 g, 0.094 mmole), dimethylaminipyridine (0.001 g, 0.11equivalents), triethylamine (0.022 g, 0.215 mmole) and 5 ml drydichloromethane are stirred at room temperature for 12 hours. Thesolvent is removed in vacuo, and the remaining oil redissolved in 0.025ml ethyl acetate. This solution is added to a micro flash silica columnin a disposable pasteur pipette and the product eluted with 2:1hex/ethyl acetate (0.040 g, 92%). By ¹ H-NMR, the ratio of RR/RSdiasteriomers is 67/1-97% ee.

NMR: (CDCl₃) 3.57,dd, 1H;3.68,dd,1H;3.69,s,6H;3.70,d,3H;3.83,s,3H;6.04,dd,1H;6.36,s,2H;7.3-7.45,m, 5H. [α]²¹D=-28.4^(m) 1% CHCl₃ M.S.: (IBu) 508,275,273 (base). Melting Point:99°-101° C. C,H Analysis: (theoretical, actual) C (49.72,49.81), H(4.37,4.40).

Step C: Preparation of(S)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane-2-thione (D")

Lithium hydroxide monohydrate (0.6 g, 1.27 mmole) is added to 8.5 mlcarbon disulfide and 0.2 ml DMF and is stirred for 15 minutes underreflux. To this mixture is added (R)-2-bromo-1-(3,4,5-trimethoxy-phenyl)ethanol (B") (0.1 g, 0.344 mmole). The reaction mixture is refluxedunder an N₂ atmosphere for 24 hours. The solvent is removed in vacuo,and the remaining oil redissolved in ethyl acetate, washed with 10% NaOHand H₂ O. The organic layer is dried over MgSO₄, filtered, andevaporated to an oil which is purified by flash column chromatographyusing 1:1 hexane/ethyl acetate as eluent. (0.034 g, 33%: [α]²¹D=+90.5^(m) 1% CHCl₃). NMR: (CDCl₃) 3.85,s,3H;3.88,s,6H;3.99,dd,1H;4.17,t,1H;5.57,dd,1H;6.70,s,2H.

Step D: Preparation of (S)-1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol(E")

Lithium aluminum hydride (0.146 g, 3.84 mole) is added to 20 ml drydiethyl ether. To this slurry is added(s)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane-2-thione (D") (0.725 g,2.40 mmole) predissolved in 30 ml dry THF. The reaction is stirred atroom temperature under an N₂ atmosphere for 24 hours. The reaction iscooled to 0° C. and the excess hydride destroyed with H₂ O. The reactionmixture is acidified with 10% HCl and immediately extracted with diethylether. The organic layer is washed with H₂ O, dried over MgSO₄, filteredand evaporated to a whine solid (0.514 g, 82%).

[α]²¹ D=+42.3^(s) 1% CHCl₃. NMR: (CDCl₃) 3.84,s,3H;3.87,s,6H;3.98,dd,1H;4.13,dd,1H;5.58,dd,1H;6.69,s,2H.

The Mosher ester derivation of(S)-1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (F") was made asfollows. (S)-1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (E") (0.004 g,0.015 mole), (R) (+)-α-methoxy-α-(trifluoromethyl) phenylacetic acidchloride (0.012 g, 0.04 mmole), dimethylaminopyridine (0.001 g),triethylamine (0.004 g, 0.04 mmole) and 4 ml dry dichloromethane arestirred at room temperature for 5 hours. The solvent is removed invacuo, and the remaining oil redissolved in 0.5 ml ethyl acetate. Thissolution is added no a micro flash silica column in a disposable pasteurpipette and the product eluted with 1:1 hex/ethyl acetate (0.008 g,90%). By ¹ H-NMR, the ratio of RR/RS diastereomers is 11:1 (84% ee).NMR: (CDCl₃) (mixture of diastereomers)3.2-3.4,m,2H;3.55-3.70,m,2H;3.30,d,3H;3.44,d,3H;3.48,d,3H;3.51,d,3H;3.74,s,6H;3.80,s,3H;3.81,s,6H;3.83,s,3H;4.63,dt,2H;6.43,s,2H;6.46,s,2H;7.29-7.54,m,10H. M.S.: (IBu) 693 (base),443,391.

Step E: Preparation of(R,S)-2-(3-hydroxy-5-iodo-4-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(G")

(S)-1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (E") (0.500 g, 1.92mmole]), 4-hydroxy-5-iodo-3-methoxybenzaldehyde (0.486 g, 1.75 mmole)and 0.176 g of pyridinium paratoluene sulfonate are added to 50 ml drybenzene and refluxed with Dean-Stark removal of the benzene-waterazeotrope for 12 hours. The benzene is removed in vacuo, and theremaining oil redissolved in dichloromethane. The organic layer iswashed with 10% NaHCO₃ and H₂ O. The organic layer is dried over MgSO₄,filtered, and evaporated in vacuo to an oil which is purified by flashcolumn chromatography with 2:1 hex/ethyl acetate as eluent. The productmixture contains a 1.0/1.2 cis/trans ratio (0.800 g, 88%). The transisomer is isolated after four recrystallizations from methanol (0.100g).

NMR: (CDCl₃) 3.49,dd,1H;3.64,dd,1H;3.84,s,3H;3.88,s,6H;3.93,s,3H;5.05,dd,1H;5.76,s,1H;6.11,s,1H;6.72,s,2H;7.10,d,1H;7.50,d,1H. M.S.: (IBu) 520 (100%) Melting Point:145°-146° C. [α]²¹ D=+19.5^(s) 1% CHCl₃.

FIGS. 5a and 5b show chemical structures of dimeric2,4-diaryl-1,3-dithiolane compounds. Erez et al., in J. Med. Chem., 25,847-849 (1982), reported an increase in the binding activity of bivalentligands versus their monomer counterparts in some biological systems(specifically, opioid receptors. Several dimeric2,4-diaryl-1,3-dithiolane compounds have been synthesized and thesubstituent groups of those dimeric compounds are shown in FIGS. 6a and6b which, respectively, relate to the dimeric compounds shown in FIGS.5a and 5b. In addition, the antagonist activity for PAF induced plateletaggregation for one of the dimeric compounds has been tested accordingto the procedures described above. Note that only a small concentrationof the dimeric compound is required to inhibit PAF induced plateletaggregation (FIG. 6b shows compounds 22d has an IC₅₀ value of 9 μM).Example 11 describes the synthesis of the dimeric2,4-diaryl-1,3-dithiolane compounds.

EXAMPLE 11 Cis andtrans-2-(3-nitro-4-hydroxy-5-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(1) (FIG. 20)

Step A Preparation of 1-(3,4,5-trimethoxyphenyl)oxirane (37) (FIG. 19)

3,4,5-trimethoxybenzaldehyde (9.80 g,50.0 mmole) was dissolved in 20 mlCH₂ Cl₂ along with tetrabutylammonium iodide (0.396 g,1.00 mmole). Tothis solution was added a cooled 50% NaOH solution (10 g NaOH in 10 mlH₂ O). To this mixture was added trimethylsulfonium iodide (10.20 g,50.0mmole). The reaction was refluxed with vigorous stirring for 15 hours.The reaction was quenched with H₂ O, extracted with CH₂ Cl₂, washed withbrine, dried over MgSO₄ and evaporated to an oil (9.69 g, 84%) whichsolidified to a white solid after 24 hours in vacuo.

NMR (CDCl₃) 2.75,dd,1H: 3.11,dd,1H: 3.81.d,1H: 3.82,s,3H; 3.85,s,6H;6.50,s,2H M.S. (CI) 211 (100%). Melting Point 54.5°-56° C. Anal. Calcd.for C₁₁ H₁₄ O₄ : C, 62.85: H, 6.76. Found C, 62.63; H, 6.76.

Step B Preparation of 4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane-2-thione(38)(FIG. 19)

Powdered potassium hydroxide (2.40 g,42.85 mmole) was dissolved in 10.0ml methanol and carbon disulfide (3.10 ml, 51.43 mmole) was added at 0°C. under an N₂ atmosphere. The reaction mixture was shaken vigorouslyand 1-(3,4,5-trimethoxyphenyl) oxirane (37) (FIG. 19) (3.50 g,16.66mmole) was added. The reaction was allowed to warm to room temperatureat which point the reaction started to reflux for twenty minutes.Subsequently, the reaction was stirred at room temperature overnight.The yellow precipitate was isolated by suction filtration and was washedwith H₂ O and diethylether to yield 3.82 g (76%).

NMR: (CDCl₃) 3.85,s,3H; 3.88,s,6H; 3.99,dd,1H; 4.17,t,1H; 5.57,dd,1H;6.70,s,2H. M.S.: (IBu) 303 (100%). Melting Point: 152°-154° C. Anal.Calcd. for C₁₂ H₁₄ O₃ S₃ : C, 47.66; H, 4.67: S, 31.80. Found: C, 47.90;H, 4.70; S, 31.71.

Step C Preparation of 1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39)(FIG. 19)

Lithium aluminum hydride (0.20 g,5.27 mmole) was added to 15 ml drydiethyl ether. To this slurry was added4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane-2-thione (38) (FIG. 19) (1.0g,3.31 mmole) predissolved in 20 ml dry THF. The reaction was refluxedunder an N₂ atmosphere for 12 hours. The reaction was cooled to 0° C.and the excess hydride destroyed with H₂ O. The reaction mixture wasacidified with 10% HCl and immediately extracted with diethyl ether. Theorganic layer was washed with H₂ O, dried over MgSO₄, and concentratedto a white solid (0.836 g, 97%).

NMR: (CDCl₃) 2.34,d,1H; 2.95,m, 1H; 3.09,m, 1H; 3.84,s,3H; 3.87,s,6H;4.03,m,1H: 6.53,s,2H. M.S. (IBu): 261 (100%). Melting Point: 72.5°-73.5°C. Anal. Calcd. for C₁₁ H₁₆ O₃ S₂ : C, 50.74: H, 6.19: S, 24.63. Found:C, 50.85; H, 6.20; S, 24.53.

Step D Preparation of cis and trans2-(4-hydroxy-3-methoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(1) (FIG. 20)

1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (25.4 g,97.7mmole), 5-nitrovanillin (16.73 g, 84.9 mmole), pyridiniumpara-toluenesulfonate (PPTS) (8.52 g, 33.9 mmole) and 100 ml dry benzenewere refluxed under an argon atmosphere with Dean-Stark removal of thebenzene-water azeotrope for 12 hours. The reaction was cooled to roomtemperature and the precipitated PPTS removed by vacuum filtration.Hexane (100 ml) was added to the filtrate and the precipitate collectedby vacuum filtration. The yellow solid was washed with cold water,followed by minimal cold methanol and finally cold diethyl ether toleave 28.62 g of a 1:1.3 cis/trans ratio of product. Sixrecrystallizations from ethyl acetate/hexane gives 4.3 g of pure transdiastereomer. An additional 2.4 g trans product can be obtained byrepeating the above crystallization process from the material remainingin the mother liquors. Once 6.7 g of trans product was isolated,0.315 gof cis diastereomer was isolated by recrystallizing the combined motherliquors from above.

Trans epimer:

NMR (CDCl₃) 3.50,dd,1H; 3.66,dd,1H; 3.84,s,3H: 3.88,s,6H; 4.00,s,3H:5.05,dd,1H; 5.80,s,1H; 6.72.s.2H; 7.41,d,1H; 7.90,d,1H. M.S. (IBu) 440(100%). Melting Point 149°-151° C. Anal. Calcd. for C₁₉ H₂₁ O₇ S₂ N: C,51.92: H, 4.82: S, 14.59. Found: C, 52.03: H, .4.86: S, 14.51.

Cis epimer:

NMR: (CDCl₃) 3.53,d, 2H; 3.84,s,3H: 3.89,s,6H; 3.97,s,3H: 4.88,t,1H;5.70,s,1H; 6.75,s,2H: 7.37,d,1H: 7.97,d, 1H. M.S. (CI) 440 (100%).Melting Point 120°-121° C. Anal. Calcd. for C₁₉ H₂₁ O₇ S₂ N: C, 51.92:H, 4.82: S, 14.59. Found: C, 52.05; H, 4.87; S, 3.12

EXAMPLE 12 Preparation of Cis andtrans-2-(3,4-dimethoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(2) (FIG. 20)

Using the Aldrich diazald kit, diazald (13.0 g, 60.7 mmole) predissolvedin 100 ml diethyl ether was added dropwise to an aqueous potassiumhydroxide solution (ethanol, 27 ml; H₂ O, 21 ml; and potassiumhydroxide, 13.3 g) at 65° C. The diazomethane/ether distillate was addedat 0° C. to a solution oftrans-2-(4-hydroxy-3-methoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(1) (FIG. 20) predissolved in 25 ml chloroform and 50 ml methanol. Thereaction was stirred to completely homogenize the solution and was thenallowed to stand at room temperature under an argon atmosphere for 5hours. The solvent was removed in vacuo and the remaining oil wasdissolved in 10 ml diethyl ether. The product crystallized out of theether solution to yield 3.285 g (98%) of light yellow crystals.

Trans epimer

NMR: (CDCl₃) 3.49,dd,1H: 3.65,dd,1H; 3.84,s,3H; 3.88,s,6H; 3.96,s,3H;3.97,s,3H; 5.04,dd,1H; 5.78,s,1H; 6.71,s,2H; 7.32,d,1H; 7.58,d,1H. M.S.(CI) 454 (100%). Melting Point 133°-134° C. Anal. Calcd. for C₂₀ H₂₃ O₇S₂ N: C, 52.97; H, 5.11; S, 14.14; N, 3.09. Found: C, 52.92: H, 5.06; S,14.06; N, 3.14.

The cis product can be obtained in the same manner as above startingfromcis-2-(4-hydroxy-3-methoxy-5-nitrophenyl)-4-(3,4,5-trimethhoxyphenyl)-1,3-dithiolane(1) (FIG. 20).

Cis epimer:

NMR: (CDCl₃) 3.55,d,2H: 3.84,s,3H; 3.88,s,6H: 3.93,s,3H; 3.97,s,3H;4.88,t,1H: 5.70,s,1H; 6.73,s,2H; 7.30,d,1H; 7.65,d,1H. M.S. (CI) 454(100%). Melting Point 99°-100° C. Anal. Calcd. for C₂₀ H₂₃ O₇ S₂ N: C,52.97; H, 5.11; S, 14.14; N, 3.09. Found: C, 53.08; H, 5.09; S, 14.04;N, 3.10.

EXAMPLE 13 Preparation of Cis andtrans-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxy-phenyl)-1,3-dithiolane(3) (FIG. 20)

Trans-2-(3,4-dimethoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(2) (FIG. 20) (3.10 g, 6.84 mmole) was predissolved in 33 ml absoluteethanol. To this solution was added calcium chloride (0.721 g, 6.50mmole) predissolved in 7 ml H₂ O followed by freshly activated zinc dust(10.0 g,195 mmole). The reaction was refluxed for 12 hours. The solidwas removed by vacuum filtration through celite and was washed withethyl acetate. The filtrate was washed with H₂ O, dried over MgSO₄, andevaporated in vacuo to a white foam (2.52 g, 87%).

Trans epimer:

NMR: (CDCl₃) 3.45,dd,1H; 3.63,dd,1H; 3.81,s,3H; 3.84,s,3H; 3.87,s,3H;3.88,s,6H; 5.04,dd,1H; 5.75,s,1H; 6.56,d, 1H; 6.65,d,1H; 6.72,s,2H. M.S.(IBu): 424, 227, 195 (100%). Melting Point 48°-51° C. (foam). Anal.Calcd. for C₂₀ H₂₅ O₅ S₂ N: C, 56.72: H, 5.95: S, 15.14: N, 3.31. FoundC, 56.79: H, 5.96; S, 15.04: N, 3.35.

The cis product can be obtained in the same manner as above startingfromcis-2-(3,4-dimethoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(2) (FIG. 20).

Cis epimer:

NMR: (CDCl₃) 3.53,d,2H; 3.81,s,3H; 3.83,s,3H; 3.85,s,3H; 3.87,s,6H;4.81,t,1H; 5.68,s,1H; 6.64,d,1H; 6.68,d, 1H; 6.74,s,2H. M.S. (CI) 424(100%), 227, 195, 119.

EXAMPLE 14 Preparation of cis andtrans-2-(3,4-dimethoxy-5-N-methylaminophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(4) (table 1)

Trans-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 20) (2.07 g,4.89 mmole), glacial acetic acid (57 μL, 1.0mmole), 37% formaldehyde (75 μL, 1.0 mmole), and dry acetonitrile (30ml) were stirred at room temperature under an argon atmosphere for 5minutes. To this solution was added sodium cyanoborohydride (0.069 g,1.1mmole) and the reaction was stirred at room temperature for 48 hours.The precipitate was removed by filtration and the filtrate quenched with10% potassium carbonate and extracted with dichloromethane. The organiclayer was washed with brine, dried over MgSO₄, and concentrated in vacuoto an oil which was purified by flash column chromatography with 2:1hex/ethyl acetate as eluent (0.400 g, 91%). The excess primary amine wasrecovered in yield.

Trans epimer:

NMR: (CDCl₃) 2.87,s,3H; 3.46,dd,1H; 3.65,dd,1H; 3.78,s,3H; 3.84,s,3H;3.87,s,3H; 3.88,s,6H; 5.07,dd,1H; 5.83,s,1H; 6.51,d,1H; 6.59,d,1H;6.73,s,2H;. M.S. (CI): 438 (100%).

The cis product can be obtained in the same manner as above startingfromcis-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 20).

EXAMPLE 15 Preparation of cis andtrans-2-(3,4-dimethoxy-5-N,N-dimethylaminophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(5) (FIG. 20)

Trans-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 20) (0.031 g,0.073 mmole), 37% formaldehyde (60 uL), andsodium cyanoborohydride (0.014 g,0.220 mmole) were dissolved in dryacetonitrile (2 ml). To this solution at room temperature under an argonatmosphere was added glacial acetic acid (83 μL). The reaction wasstirred at room temperature for 24 hours. The precipitate was removed byfiltration and the filtrate quenched with 10% potassium carbonate andextracted with dichloromethane. The organic layer was washed with brine,dried over MgSO₄, and concentrated in vacuo to an oil which was purifiedby flash column chromatography with 2:1 hex/ethyl acetate as eluent(0.017 g, 52%). The compound can be recrystallized from hexane/ethylacetate to a white solid.

Trans epimer:

NMR: (CDCl₃) 2.84,s,6H; 3.46,dd,1H; 3.55,dd,1H; 3.80,s,3H; 3.84,s,3H;3.88,s,9H; 5.07,dd,1H; 5.83,s,1H; 6.73,s,3H; 6.83,d,1H. M.S. (CI) 452,226, 195, 83 (100%). Melting Point 89°-91° C. Anal. Calcd. for C₂₂ H₂₉O₅ S₂ N: C, 58.51; H, 6.47; S, 14.20; N, 3.10. Found: C, 58.60; H, 6.47;S, 14.13; N, 3.13.

The cis product can be obtained in the same manner as above startingfromcis-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 20).

Cis epimer: NMR: (CDCl₃) 2.83,s,6H; 3.55,d,2H; 3.79,s,3H; 3.83,s,3H;3.87,s,9H; 4.83,t,1H; 5.73,s,1H; 6.76,bs,3H; 6.85,d, 1H. M.S. (CI): 452,226, 117 (100%).

EXAMPLE 16 Preparation of cis andtrans-N'-hydroxyl-N'-methyl-N-[2,3-dimethoxy-5-{3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl}]phenylurea (6) (FIG. 21)

Trans-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 20) (0.150 g,0.355 mmole), triethylamine (50 μL), triphosgene(0.035 g,0.118 mmole), and 20 ml dry dichloromethane were refluxed for 2hours under an argon atmosphere. When all of the amine had beenconverted to isocyanate by TLC, the reaction was cooled to roomtemperature and N-methyl hydroxylamine hydrochloride (0.044 g,0.533mmole) predissolved in 5 ml THF, 75 μL triethylamine, and 0.5 ml H₂ Owas added. The reaction was stirred at room temperature overnight underan argon atmosphere. The solvent was removed in vacuo, the remaining oilredissolved in dichloromethane. The organic layer was washed with H₂ O,dried over MgSO₄, and concentrated to an oil in vacuo which was purifiedby flash column chromatography with 2:1 hexane/ethyl acetate as eluent.(112 mg, 64% yield foam). The product can be crystallized fromhexane/ethyl acetate to a white solid.

Trans epimer:

NMR: (CDCl₃) 3.28,s,3H; 3.45,dd,1H; 3.65.dd,1H; 3.84,s,3H; 3.85,s,3H;3.88,s,6H; 3.90,s,3H; 5.09,dd,1H; 5.72,s,1H; 6.72,s,2H; 6.90,d,1H;8.15,d,1H; 8.52.s,1H. M.S. (CI): Melting Point 93°-94° C. Anal. Calcd.for C₂₂ H₂₈ O₇ S₂ N₂ : C, 53.21; H, 5.68; S, 12.91; N, 5.66. Found: C,53.31; H, 5.70; S, 12.84; N, 5.60.

The cis product can be obtained in the same manner as above startingfromcis-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 20).

Cis epimer:

NMR: (CDCl₃) 3.25,s,3H; 3.55,d,2H; 3.83.s,3H; 3.84,s,3H; 3.88,s,9H;4.84,dd,1H; 5.71,s,1H; 6.78,s,2H; 6.89,d, 1H; 8.23,d, 1H; 8.52,s,1H.M.S. (CI): 497, 450,424, 227, 147.

EXAMPLE 17 Preparation of cis andtrans-2-(5-acetamido-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(7) (table 1)

Trans-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 20) (25 mg) was dissolved in 5 ul dry dichloromethane andcooled to 0° C. under an argon atmosphere. To this solution was addedacetic anhydride (11 μL) followed by 1 drop glacial acetic acid. Thereaction was allowed to warm to room temperature overnight. The reactionwas quenched with 10% NaHCO₃ and extracted with dichloromethane. Theorganic layer was dried over MgSO₄, and concentrated to an oil which waspurified by flash column chromatography using 2:1 hexane/ethyl acetateas eluent (24 mg, 89% yield).

Trans epimer:

NMR: (CDCl₃) 2.21,s,3H; 3.46,dd,1H; 3.67,dd,1H; 3.84,s,3H; 3.87,s,3H;3.88,s,6H; 3.91,s,3H; 5.08,dd,1H; 5.82,s,1H; 6.72,s,2H; 6.97,d, 1H;7.78,bs,1H; 8.8.24,d, 1H. M.S. (CI): 466, 117 (100%).

The cis product can be obtained in the same manner as above startingfromcis-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 20).

EXAMPLE 18Cis/trans-2-(3-methoxy-4-propoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(8) (table 1)

Step A Preparation of 3-methoxy-5-nitro-4-propoxybenzaldehyde (40)

5-nitrovanillin (2.50 g,12.69 mmole) and freshly pulverized potassiumcarbonate (5.25 g,38.07 mmole) were added to 40 ml dry DMF and stirredat room temperature for 5 minutes. Propyl iodide (4.31 g,25.38 mmole)was added to the reaction mixture which was stirred under an N₂atmosphere at 60° C. for 36 hours. The reaction mixture was quenchedwith 125 ml H₂ O and extracted with dichloromethane. The organic layerwas washed with ss NaCl, dried over MgSO₄ and the solvent removed invacuo to leave a yellow oil. (1.71 g, 56%).

NMR: (CDCl₃) 1.03,t,3H; 1.81,m,2H; 3.97,s,3H; 4.21,t,2H; 7.59,d, 1H;7.80,d, 1H; 9.90,s,1H. M.S.: (IBu) 240 (100%).

Step B Preparation ofcis/trans-2-(3-methoxy-4-propoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(8) (table 1)

1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (0.689g,2.65 mmole), 3-methoxy-5-nitro-4-propoxybenzaldehyde (40) (0.633 g,2.65 mmole) and 0.266 g of pyridinium para-toluenesulfonate was added to50 ml dry benzene and refluxed with Dean-Stark removal of the benzene-water azeotrope for 24 hours. The benzene was removed in vacuo, and theremaining oil redissolved in dichloromethane and was purified by flashcolumn chromatography with 9:1 hex/ethyl acetate as eluent. The productmixture contains a 1/1 cis/trans ratio (0.600 g, 47%).

cis/trans epimers:

NMR: (CDCl₃) 0.98,t,6H; 1.76,m,4H; 3.46,dd,1H; 3.52,d,2H; 3.62,dd,1H;3.81,s,6H; 3.84,s,12H; 3.98,s,3H; 3.91,s,3H; 4.05,t,4H; 4.86,t,1H;5.03,dd,1H; 5.67,1H; 5.76,s,1H; 6.70,s,2H; 6.72,s,2H; 7.28,t,2H;7.53,d,1H; 7.60,d,1H. M.S. (CI): 482, 288, 268, 240 (100%), 227, 198.

EXAMPLE 19 Preparation ofcis/trans-2-(5-amino-3-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(9) (Table 1)

1:1Cis/trans-2-(3,4-dimethoxy-5-nitrophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(8) (Table 1) (0.40 g,0.832 mmole), calcium chloride (0.088 g,0.790mmole), freshly activated zinc dust (1.70 g,33.26 mmole) and 30 ml 83%ethanol were refluxed for 4 hours. The solid was removed by vacuumfiltration and the filtrate concentrated to an oil in vacuo. The oil wasredissolved in dichloromethane, dried over MgSO₄, and purified by flashcolumn chromatography using 2:1 hex/ethyl acetate as eluent. The productmixture (foam) contains a 1.0/1.0 cis/trans ratio (0.302 g, 81%).

cis/trans epimers

NMR: (CDCl₃) 1.02,t,6H; 1.77,m,4H; 3.45,dd,1H; 3.53,d,2H; 3.62,dd,1H;3.83-3.87, 4s, 24H; 3.91,t,4H; 4.81,t,1H; 5.02,dd,1H; 5.68,s,1H;5.75,s,1H; 6.55,d,1H; 6.58,d, 1H; 6.64,d, 1H; 6.68,d, 1H; 6.71,s,2H;6.75,s,2H. M.S. (CI): 452, 195 (100%).

EXAMPLE 20 Preparation ofcis/trans-2-(5-dimethylamino-3-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(10) (Table 1)

1:1cis/trans-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(9) (Table 1) (0.100 g,0.222 mmole), 37% formaldehyde (177 uL), andsodium cyanoborohydride (0.044 g,0.700 mmole) were dissolved in dryacetonitrile (4 ml). To this solution at room temperature under an argonatmosphere was added glacial acetic acid (250 μL). The reaction wasstirred at room temperature for 24 hours. The precipitate was removed byfiltration and the filtrate quenched with 10% potassium carbonate andextracted with dichloromethane. The organic layer was washed with brine,dried over MgSO₄, and concentrated in vacuo to an oil which was purifiedby flash column chromatography with 2:1 hex/ethyl acetate as eluent. Theproduct mixture (oil) contains a 1.0/1.0 cis/trans ratio (0.050 g, 47%).

cis/trans epimers:

NMR: (CDCl₃) 1.01,t,3H; 1.76,m,4H; 2.82,s,3H; 2.83,s,3H; 3.46,dd,1H;3.62,d,2H; 3.66,dd,1H; 3.84-3.88, 4s, 24H; 4.83,t,1H; 5.07,dd,1H;5.75,s,1H; 5.83,s,1H; 6.73,s,3H; 6.76,s,3H; 6.82,dd,1H; 6.84,dd,1H. M.S.(CI): 480, 195 (100%).

EXAMPLE 21Cis/trans-2,3-dimethoxy-5-[3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl]phenylcarboxylic acid (11) (Table 1)

Step A Preparation of 3,4-dimethoxy-5-iodobenzaldehyde (41) (FIG. 22)

5-iodovanillin (6.0 g, 21.58 mmole), potassium carbonate (5.96 g, 43.16mmole), iodomethane (9.06 g, 64.77 mmole) and dry DMF (50 ml) werestirred at room temperature under an argon atmosphere overnight. Thereaction was quenched with 250 ml H₂ O and extracted with diethyl ether.The organic layer was dried over MgSO₄, and concentrated to an oil invacuo which was purified by flash column chromatography using 3:1hexane/ethyl acetate as eluent. The column gives 5.814 g (92%) of awhite solid.

NMR: (CDCl₃) 3.92,s,6H; 7.40,s,1H; 7.84,s,1H; 9.82,s,1H.

Step B Preparation of 2-(3,4-dimethoxy-5-iodophenyl)-1,3-dioxane (42)(FIG. 22)

3,4-dimethoxy-5-iodobenzaldehyde (41) (FIG. 22) (5.814 g,19.9 mmole),1,3-propanediol (6.13 g, 79.6 mmole), pyridinium para-toluenesulfonate(2.0 g, 7.96 mmole) and 100 ml dry benzene were refluxed with Dean-Starkremoval of the benzene-water azeotrope overnight. The benzene wasremoved in vacuo and the remaining oil redissolved in diethyl ether andwas washed with 10% NaHCO₃ and H₂ O. The organic layer was washed overMgSO₄, and concentrated to a white solid in vacuo. (6.823 g, 98%). Thesolid can be recrystallized from hexane/ethyl acetate.

NMR (CDCl₃) 1.45,d,1H; 2.20,m,1H; 3.80,s,3H; 3.87,s,3H; 3.96,dt,2H;4.25,dd,2H; 5.40,s,1H; 7.04,d,1H; 7.46,d,1H. M.S. (CI) 351 (100%)Melting Point 76°-77.5° C. Anal. Calcd. for C₁₂ H₁₅ O₄ I C, 41.16;H,4.32: I, 36.24. Found C, 41.30; H, 4.33; I, 36.15.

Step C Preparation of 2,3-dimethoxy-5-formylbenzoic acid (43) (FIG. 22)

2-(3,4-dimethoxy-5-iodophenyl)-1,3-dioxane (42) (FIG. 22) (1.7 g, 4.86mmole) was dissolved in 40 ml dry THF and cooled to -78° C. under anargon atmosphere. n-butyllithium (4.3 ml of a 1.25M soln.) was added andthe reaction was warmed to 0° C. and was stirred at that temperature foran additional 45 minutes. The aryl lithium solution was then poured ontosolid carbon dioxide covered with anhydrous diethyl ether. A whiteprecipitate formed immediately. Water was added and the organic solventsubsequently removed in vacuo. The remaining aqueous solution wasextracted with ethyl acetate. The organic layer was washed with 5%sodium thiosulfate, water, and then stirred vigorously over anequivolume of 10% HCl overnight. The organic layer was separated and theproduct extracted into 10% K₂ CO₃. The basic solution was acidified with10% HCl and the product extracted into chloroform. The organic layer wasdried over MgSO₄, and concentrated in vacuo to a white solid (0.412 g,40%). The solid can be recrystallized from hexane/ethyl acetate.

NMR: (CDCl₃) 3.99,s,3H; 4.19,s,3H; 7.67,s,1H; 8.23,s,1H; 9.95,s,1H. M.S.(CI): 211 (100%) Melting Point 154°-155° C. Anal. Calcd. for C₁₀ H₁₀ O₅: C, 57.14: H,4.80. Found: C, 57.06; H, 4.84.

Step D Preparation ofcis/trans-2,3-dimethoxy-5-[3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl]phenylcarboxylic acid (11) (Table 1)

2,3-dimethoxy-5-formylbenzoic acid (43) (FIG. 22) (1.775 g,8.45 mmole),1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (2.51 g, 9.65 mmole) (39)(FIG. 19), pyridinium para-toluenesulfonate (0.848 g, 3.38 mmole) and100 ml dry benzene were refluxed under an argon atmosphere withDean-Stark removal of the benzene-water azeotrope for 7 hours. Thebenzene was removed in vacuo and the remaining oil purified by flashcolumn chromatography using 2:1 ethyl acetate/hexane as eluant. Thecolumn yields 2.90 g (76%, 1:1 cis/trans) of a colorless oil whichtiturates to a white solid in cold methanol. The solid can berecrystallized from hexane/ethyl acetate.

cis/trans epimers:

NMR: (CDCl₃) 3.50,dd,1H; 3.57,d,2H; 3.66,dd,1H; 3.84,s,6H; 3.88,s,12H;3.93,s,3H; 3.97,s,3H; 4.08,s,6H; 4.87,dd,1H; 5.08,dd, 1H; 5.73,s,1H;5.82,s,1H; 6.72,s,2H; 6.76,s,2H; 7.39,d, 1H; 7.42,d, 1H; 7.90,d, 1H;8.0,d,1H; 11.3,bs,1H. M.S. (CI): 453 (100%) Melting Point 130°-132° C.Anal. Calcd. for C₂₁ H₂₄ O₇ S₂ : C, 55.74; H,5.34; S, 14.17. Found: C,55.73; H, 5.38; S, 14.10.

EXAMPLE 22 Preparation ofcis/trans-N-hydroxyl-N-methyl-[2,3-dimethoxy-5-{3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl}]phenylamide (12) (Table 1)

1:1cis/trans-2,3-dimethoxy-5-[3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl]phenylcarboxylic acid (11) (Table 1) (0.650 g, 1.44 mmole), dry DMF (111 μL)and 20 ml dry dichloromethane was cooled to 0° C. under an argonatmosphere. Oxalyl chloride (314 μL, 3.6 mmole) was added and thereaction stirred for 2 hours at 0° C. The acid chloride solution wasthen added to a solution of N-methylhydroxylamine hydrochloride (0.481g, 5.76 mmole) predissolved in THF (17 ml), triethylamine (1.2 ml) andwater (1.7 ml). The reaction was stirred at room temperature for 48hours. The reaction was quenched with 10% HCl and extracted withdichloromethane. The organic layer was dried over MgSO₄, andconcentrated in vacuo to an oil which was purified by flash columnchromatography using 2:1 ethyl acetate/hexane as eluent. The columnyields 281 mg (41%) as a white foam (1:1 cis/trans).

cis/trans epimers

NMR: (CDCl₃) 3.24,s,6H; 3.50,dd,1H; 3.57,d,2H; 3.65,dd,1H;3.80-3.93,5s,30H; 4.85,dd,1H; 5.05,dd,1H; 5.73,s,1H; 5.80,s,1H;6.71,s,2H; 6.74,s,2H; 7.15,d,1H; 7.21,d, 1H; 7.25,d, 1H; 7.28,d, 1H;8.56,bs,1H. M.S. (CI): 482, 391 (100%)

EXAMPLE 23Cis/trans-2,6-dimethoxy-4-[3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl]phenylcarboxylic acid (13) (Table 1)

Step A Preparation of 2-(3,5-dimethoxyphenyl)-1,3-dioxane (44) (FIG. 23)

3,5-dimethoxybenzaldehyde (5.00 g,30.12 mmole), 1,3-propanediol (9.15 g,120.5 mmole), pyridinium para-toluenesulfonate (3.02 g, 12.05 mmole) and80 ml dry benzene were refluxed with Dean-Stark removal of thebenzene-water azeotrope for 12 hours. The benzene was removed in vacuoand the remaining oil redissolved in dichloromethane and was washed with10% NaHCO₃ and H₂ O. The organic layer was washed over Na₂ SO₄ andconcentrated to an oil in vacuo which was purified by flash columnchromatography using 2:1 hexane/ethyl acetate containing 0.5%triethylamine as eluent. (5.731 g, 85%).

NMR: (CDCl₃) 1.45,dt,1H; 2.22,m, 1H; 3.79,s,6H; 3.97,dt,2H; 4.26,dd,2H;5.43,s,1H; 6.43,t,1H; 6.65,d,2H. M.S. (CI): 225 (100%)

Step B Preparation of 2,6-dimethoxy-4-formylbenzoic acid (45) (FIG. 23)

Anhydrous TMEDA (2.05 ml, 13.62 mmole) and 90 ml dry THF was cooled to-78° C. under an argon atmosphere. n-Butyllithium (11.35 ml of a 1.20Msoln.) was added and after 15 minutes,2-(3,5-dimethoxyphenyl)-1,3-dioxane (44) (FIG. 23) (3.05 g, 13.62 mmole)predissolved in 50 ml dry THF was added. The reaction was warmed to 0°C. and was stirred at that temperature for an additional 60 minutes (thesolution turned from a blood red color to a dark brown color). The aryllithium solution was then poured onto solid carbon dioxide covered withanhydrous diethyl ether. A white precipitate formed immediately. Whenthe reaction warmed to room temperature, 15 ml of 10% HCl was added andthe reaction was stirred overnight. The product was then extracted intochloroform. The organic layer was dried over MgSO₄, and concentrated invacuo to a white solid (1.311 g, 46%). The solid can be recrystallizedfrom hexane/ethyl acetate.

NMR: (CDCl₃) 3.95,s,6H; 7.11,s,2H; 9.97,s,1H. M.S. (CI) 211 (100%)Melting Point 209°-211° C. Anal. Calcd. for C₁₀ H₁₀ O₅ : C, 57.14;H,4.80. Found: C, 5.7.24; H, 4.82.

Step C Preparation ofcis/trans-2,6-dimethoxy-4-[3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl]phenylcarboxylic acid (13) (Table 1)

2,6-dimethoxy-4-formylbenzoic acid (45) (FIG. 23) (1.18 g, 5.62 mmole),1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (1.68 g,6.46 mmole), pyridinium para-toluenesulfonate (0.564 g, 2.25 mmole) and50 ml dry benzene were refluxed under an argon atmosphere withDean-Stark removal of the benzene-water azeotrope for 8 hours. Thebenzene was removed in vacuo and the remaining oil purified by flashcolumn chromatography using 2:1 ethyl acetate/hexane as eluent. Thecolumn yields 1.25 g (49%, 11 cis/trans) of a white foam. The solid canbe recrystallized from dichloromethane/diethyl ether.

cis/trans epimers:

NMR: (CDCl₃) 3.50,dd,1H; 3.57,d,2H; 3.66,dd,1H; 3.84,s,3H; 3.84,s,3H;3.86,s,6H; 3.88,s,6H; 3.91,s,6H; 3.93,s,6H; 4.88,t,1H; 5.03,dd,1H;5.73,s,1H; 5.80,s,1H; 6.72,s,2H; 6.72,s,2H; 6.87,s,2H; 6.88,s,2H. M.S.(CI): 453 (100%) Melting Point 124°-125° C. Anal. Calcd. for C₂₁ H₂₄ O₇S₂ : C, 55.74: H,5.34; S, 14.17. Found: C, 55.45; H, 5.41: S, 14.32.

EXAMPLE 24 Preparation ofcis/trans-N-hydroxyl-N-methyl-[2,6-dimethoxy-4-{3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl}]phenylamide (14) (table 1)

1:1cis/trans-2,6-dimethoxy-4-[3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl]phenylcarboxylic acid (13) (table 1) (0.630 g, 1.30 mmole), dry DMF (111 μL)and 20 ml dry dichloromethane was cooled to 0° C. under an argonatmosphere. Oxalyl chloride (314 μL, 3.6 mmole) was added and thereaction stirred for 2 hours at 0° C. The acid chloride solution wasthen added to a solution of N-methylhydroxylamine hydrochloride (0.962g, 11.52 mmole) predissolved in THF (20 ml), triethylamine (2.4 ml) andwater (2.0 ml). The reaction was stirred at room temperature overnight.The reaction was quenched with 10% HCl end extracted with chloroform.The organic layer was dried over MgSO₄, and concentrated in vacuo to anoil which was purified by flash column chromatography using 2:1 ethylacetate/hexane as eluent. The column yields 335 mg (54%) as a white foam(1:1 cis/trans).

cis/trans epimers

NMR: (CDCl₃) 3.13,s,6H; 3.45,dd,1H; 3.50,d,2H; 3.59,dd,1H; 3.3.77,s,6H;3.77,s,6H; 3.78,s,6H; 3.79,s,6H; 3.81,s,6H; 4.81,t,1H; 5.00,dd,1H;5.68,s,1H; 5.76,s,1H; 6.68,s,2H; 6.69,s,2H; 6.78,bs,4H. M.S. (CI) 482,391,89 (100%) Melting point 148°-153° C. Anal. Calcd. for C₂₂ H₂₇ O₇ S₂N C, 54.87; H, 5.65; S, 13.32; N, 2.91. Found C, 54.98; H, 5.69; S,13.21; N, 2.89.

EXAMPLE 25Cis/trans-ethyl-4'-[2,6-dimethoxy-4-{3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl}]phenoxybutyrate(15) (table 1)

Step A Preparation of ethyl-4'-(2,6-dimethoxy-4-formyl)phenoxybutyrate(46)

Syringe aldehyde (2.00 g, 11.0 mmole), potassium carbonate (3.96 g,28.69 mmole), sodium iodide (2.46 g, 16.4 mmole), ethyl 4-bromobutyrate(5.559 g, 28.5 mmole) and 15 ml dry DMF were stirred under a nitrogenatmosphere at 70° C. for 24 hours. The reaction was quenched with 100 mlH₂ O and extracted with dichloromethane. The organic layer was driedover MgSO₄, and concentrated to an oil which was purified by flashcolumn chromatography using 2:1 hexane/ethyl acetate as eluent. Thecolumn yielded 2.689 g (83%) as a colorless oil.

NMR: (CDCl₃) 1.25,t,3H; 2.05,m,2H; 2.60,t,2H; 3.90,s,6H; 4.12,m,4H;7.11,s,2H; 9.86,s,1H. M.S. (CI): 297,251, 115 (100%)

Step B Preparation ofcis/trans-ethyl-4'-[2,6-dimethoxy-4-{3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl}]phenoxybutyrate(15) (table 1)

ethyl-4'-(2,6-dimethoxy-4-formyl)phenoxybutyrate (46) (0.825 g, 2.79mmole), 1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19)(0.833 g, 3.205 mmole), pyridinium para-toluenesulfonate (0.280 g, 1.116mmole) and 50 ml dry benzene were refluxed under an argon atmospherewith Dean-Stark removal of the benzene-water azeotrope overnight. Thebenzene was removed in vacuo and the remaining oil purified by flashcolumn chromatography using 1:2 ethyl acetate/hexane as eluent. Thecolumn yields 1.346 g (90%, 1:1 cis/trans) of a colorless oil.

cis/trans epimers:

NMR: (CDCl₃) 1.23,t,6H; 2.02,m,4H; 2.59,t,4H; 3.47,dd,1H; 3.55,d,2H;3.64,dd,1H; 3.84-3.87,5s,30H; 3.99,t,4H; 4.13,q,4H; 4.83,t,1H; 5.05,dd,1H; 5.74,s,1H; 5.82,s,1H; 6.72,s,2H; 6.75,s,2H; 6.81,s,2H; 6.83,s,2H.M.S. (CI) 538 (100%)

EXAMPLE 26 Preparation ofcis/trans-4'-[2,6-dimethoxy-4-{3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl}]phenoxybutyricacid (16) (table 1)

1:1Cis/trans-ethyl-4'-[2,6-dimethoxy-4-{3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl}]phenoxybutyrate(15) (table 1) (1.346 g, 2.5 mmole) was dissolved in 15 ml THF. To thissolution was added lithium hydroxide monohydrate (136 mg, 3.25 mmole)predissolved in 3 ml H₂ O. The reaction was stirred at room temperatureovernight. 10% HCl was added and the product was extracted intochloroform. The organic layer was dried over MgSO₄ and concentrated invacuo to an oil which was purified by flash column chromatography using100% ethyl acetate as eluent to give 715 mg (56%) of a white foam (1:1cis/trans).

cis/trans epimers:

NMR: (CDCl₃) 2.04,m,4H; 2.69,t,4H; 3.47,dd,1H; 3.54,d,2H; 3.64,dd,1H;3.84-3.87,5s,30H; 4.00,t,4H; 4.13, g,4H; 4.83,t,1H; 5.06,dd,1H;5.74,s,1H; 5.82,s,1H; 6.72,s,2H; 6.75,s,2H; 6.81,s,2H; 6.84,s,2H. M.S.(CI) 511 (100%)

EXAMPLE 27 Preparation ofcis/trans-N-hydroxyl-N-methyl-4'-[2,6-dimethoxy-4-{3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl}]phenoxybutyramide(17) (table 1)

1:1cis/trans-4'-[2,6-dimethoxy-4-{3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl}]phenoxybutyricacid (16) (table 1) (0.215 g, 0.421 mmole), dry DMF (33 μL) and 20 mldry dichloromethane was cooled to 0° C. under an argon atmosphere.Oxalyl chloride (110 μL, 1.26 mmole) was added and the reaction stirredfor 1 hour at 0° C. The acid chloride solution was then added to asolution of N-methylhydroxylamine hydrochloride (0.421 g,5.04 mmole)predissolved in THF (10 ml), triethylamine (0.765 g) and water (1.0 ml).The reaction was stirred at room temperature overnight. The reaction wasquenched with 10% HCl and extracted with chloroform. The organic layerwas dried over MgSO₄, and concentrated in vacuo to an oil which waspurified by flash column chromatography using 2:1 ethyl acetate/hexaneas eluent. The column yields 167 mg (74%) as a white foam (11cis/trans).

Cis/trans epimers:

NMR: (CDCl₃) 2.11,m,4H; 2.65,m,2H; 2.82,m,2H; 3.29,s,3H; 3.40,s,3H;3.47,dd,1H; 3.56,d,1H; 3.65,dd,1H; 3.84,s,6H; 3.86,s,12H; 3.88,s,12H;3.98,m,4H; 4.84,t,1H; 5.06,dd,1H; 5.75,s,1H; 5.82,s,1H; 6.72,s,2H;6.75,s,2H; 6.85,2s,2H. M.S. (CI) 540, 298, 195 (100%).

EXAMPLE 28 Cis andtrans-2-(3,5-dimethoxy-4-methylthiophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(18) (table 1)

Step A Preparation of 2-3,5-dimethoxy-4-methylthiophenyl)-1,3-dioxane(47) (FIG. 23)

TMEDA (898 μl,5.95 mmole) and dry THF (20 ml) were cooled to -78° C.under an argon atmosphere and 1.5M n-butyl lithium (3.96 ml) was added.The solution was kept at -78° C. for 15 minutes and then2-(3,5-dimethoxyphenyl)-1,3-dioxane (42) (FIG. 22) (1.212 g,5.41 mmole)predissolved in 10 ml dry THF was added. The solution turned blood redin color after being warmed to 0° C. and stirring at that temperaturefor 1 hour. To this solution at 0° C. was added methyl disulfide (535μl,5.95 mmole) and the reaction was stirred for two hours and thenallowed to warm to room temperature. The reaction was quenched with 10%NaHCO₃, and extracted with diethyl ether. The organic layer was driedover anhydrous sodium sulfate, and evaporated in vacuo to an oil whichwas purified by flash column chromatography using 2:1 hexane/ethylacetate as eluent. (0.957 g, 66%) (oil).

NMR: (CDCl₃) 1.46,dt,1H; 2.23,m,1H; 2.32,s,3H; 3.91,s,6H; 3.99,dt,2H;4.28,dd,2H; 5.46,s,1H; 6.71,s,2H. M.S. (CI) 271 (100%).

Step B Preparation of 3,5-dimethoxy-4-methylthiobenzaldehyde (48) (FIG.23)

2-(3,5-dimethoxy-4-methylthiophenyl)-1,3-dioxane (47) (0.945 g, 3.5mmole) was dissolved in 15 ml THF and 7 ml of 10% HCl was added. Thesolution was stirred overnight at room temperature. The aldehyde wasextracted into diethyl ether, dried over MgSO₄, and concentrated invacuo to an oil. (0.742 g, 90%).

NMR: (CDCl₃) 2.45,s,3H; 3.97,s,6H; 7.06,s,2H; 9.92,s,1H. M.S. (CI): 213(100%).

Step C Preparation of cis andtrans-2-(3,5-dimethoxy-4-methylthiophenyl)-4-(-3,4,5-trimethoxyphenyl)-1,3-dithiolane(18) (table 1)

1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (0.148 g,0.57 mmole),3,5-dimethoxy-4-methylthiobenzaldehyde (48) (FIG. 23) (0.11 g, 0.519mmole) and 0.052 g of pyridinium para-toluenesulfonate was added to 40ml dry benzene and refluxed with Dean-Stark removal of the benzene-water azeotrope for 48 hours. The benzene was removed in vacuo, and theremaining oil redissolved in dichloromethane. The organic layer waswashed with 3×30 ml H₂ O and was dried over MgSO₄, and evaporated invacuo to an oil which was purified by flash column chromatography with2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.0cis/trans ratio (0.151 g, 64%). The trans isomer was isolated after tworecrytallizations of this mixture from methanol.

trans epimer

NMR: (CDCl₃) 1.45,s,18H; 3.42-3.70,m,4H; 3.84,s,3H; 3.88,s,6H;5.10,dd,1H; 5.24,s,1H; 5.88,s,1H; 6.73,s,2H; 7.38,s,2H. M.S. (CI): 455(100%). Melting Point 140°-142.5° C. Anal. calcd. for C₂₁ H₂₆ O₅ S₃ : C,55.48; H, 5.76; S, 21.16. Found: C, 55.39; H, 5.78; S, 21.08.

EXAMPLE 29 Preparation of trans2-(4-hydroxy-5-iodo-3-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(19) (table 1)

1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (32) (FIG. 26) (0.500 g,1.92 mmole), 5-iodovanillin (0.411 g, 1.48 mmole), pyridiniumpara-toluenesulfonate (0.193 g, 0.769 mmole) and 50 ml dry benzene wererefluxed under an argon atmosphere with Dean-Stark removal of thebenzene-water azeotrope for 12 hours. The benzene was removed in vacuo,and the remaining oil redissolved in dichloromethane. The organic layerwas washed with 3×30 ml H₂ O and was dried over MgSO₄, and evaporated invacuo to an oil which was purified by flash column chromatography with2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.3cis/trans ratio (0.578 g, 75%) after one crystallization from methanol.The trans isomer (50 mg) was isolated after one additionalcrytallization from ethanol.

Trans epimer:

NMR: (CDCl₃) 3.49,dd,1H; 3.64,dd,1H; 3.84,s,3H; 3.88,s,6H; 3.93,s,3H;5.05,dd,1H; 5.76,s,1H; 6.11,s,1H; 6.72,s,2H; 7.10,d,1H; 7.50,d,1H. M.S.(IBu) 521 (100%). Melting Point 145°-146° C. Anal. calcd. for C₁₉ H₂₁ O₅S₂ I: C, 43.85; H, 4.07; S,12.32. Found: C, 43.93; H, 4.09; S, 12.42.

EXAMPLE 30 Preparation of cis/trans2-(3,4-dimethoxy-5-iodophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(20) (table 1)

1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (1.404g,5.40 mmole), 3,4-dimethoxy-5-iodobenzaldehyde (41) (FIG. 22) (1.30 g,4.45 mmole) and 0.542 g of pyridinium para-toluenesulfonate was added to50 ml dry benzene and refluxed with Dean-Stark removal of the benzene-water azeotrope for 12 hours. The benzene was removed in vacuo, and theremaining oil redissolved in ethyl acetate. The organic layer was washedwith 10% NaHCO₃ and H₂ O. The organic layer was dried over MgSO₄, andevaporated in vacuo to an oil which was purified by flash columnchromatography with 2:1 hex/ethyl acetate as eluent. The product mixturecontains a 1.0/1.0 cis/trans ratio (2.38 g, 100%). The trans isomer canbe isolated by recrystallization from methanol.

Trans epimer:

NMR: (CDCl₃) 3.47,dd,1H; 3.63,dd,1H; 3.82,s,3H; 3.84,s,3H; 3.88,s,9H;5.05,dd,1H; 5.74,s,1H; 6.72,s,2H; 7.26,d,1H; 7.56,d,1H. M.S. (CI): 534,501, 409, 309, 227, 195 (100%). Melting Point 117°-118° C.(Recrystallized from methanol). Anal. calcd. for C₂₀ H₂₃ O₅ S₂ I: C,44.95; H, 4.34; S, 12.00. Found: C, 45.01; H, 4.35; S, 12.08.

EXAMPLE 31 Cis/trans2-(5-cyano-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(21) (table 1)

Step A Preparation of 5-cyano-3,4-dimethoxybenzaldehyde (47) (FIG. 22)

3,4-dimethoxy-5-iodobenzaldehyde (41) (FIG. 22) (4.40 g, 15.07 mmole),copper cyanide (13.5 g, 150.7 mmole) and dry DMF (45 ml) were stirredunder an argon atmosphere for 18 hours at 140° C. The reaction wascooled to room temperature, filtered through celite, and the filtrateconcentrated to an oil in vacuo. The dark brown oil was purified througha short flash silica column using 11 hexane/ethyl acetate as eluent toyield 2.87 g (69%) of a white solid.

NMR: (CDCl₃) 3.96,s,3H; 4.18,s,3H; 7.61,d, 1H; 7.64,d, 1H; 9.87,s,1H.M.S. (CI): 383, 192 (100%).

Step B Preparation of cis/trans2-(5-cyano-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(21)

1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (2.36 g, 9.09 mmole),5-cyano-3,4-dimethoxybenzaldehyde (49) (1.50 g, 7.85 mmole) and 0.788 gof pyridinium para-toluenesulfonate was added to 50 ml dry benzene andrefluxed with Dean-Stark removal of the benzene-water azeotrope for 24hours. The benzene was removed in vacuo, and the remaining oilredissolved in ethyl acetate. The organic layer was washed with 10%NaHCO₃ and H₂ O. The organic layer was dried over MgSO₄, and evaporatedin vacuo to an oil which was purified by flash column chromatographywith 2:1 hex/ethyl acetate as eluent. The product mixture contains a1.0/1.0 cis/trans ratio (2.91 g, 86%).

Trans/cis epimers: NMR: (CDCl₃) 3.49,dd,2H; 3.56,d,4H; 3.65,dd,2H;3.84,s,6H; 3.87,s,12H; 3.89,s,3H; 3.92,s,3H; 4.02,s,6H; 4.86,t,1H;5.04,dd,1H; 5.68,s,1H; 5.75,s,1H; 6.71,s,2H; 6.72,s,2H; 7.32,bd,2H;7.37,d,1H; 7.42,d,1H. M.S. (CI) 434 (100%). Melting Point 103°-106° C.Anal. calcd. for C₂₁ H₂₃ O₅ NS₂ : C, 58.18; H, 5.35; S,14.79; N. 3.23.Found: C, 58.00: H, 5.38; S, 14.93; N, 3.21.

EXAMPLE 32Cis/trans-2-(3-(2-hydroxyethylsufonyl)-5-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane (22)

Step A Preparation of3-(2-hydroxyethylthio)-5-methoxy-4-propoxybenzaldehyde (52) (FIG. 24)

5-iodo-3-methoxy-4-propoxybenzaldehyde (6.166 g,19.27 mmole). copperpowder (10.41 g,163.78 mmole) and 45 ml DMF were stirred vigorouslyunder an N₂ atmosphere at 140° C. for 3 hours. To this slurry was added2-hydroxyethyldisulfide (4.75 g,30.8 mmole) predissolved in 10 ml DMF.The reaction was stirred at 140° C. overnight. The copper was removed bysuction filtration through celite, and was washed thoroughly with ethylacetate. The filtrate was concentrated to an oil in vacuo and thenredissolved in dichloromethane. The organic layer was washed with H₂ O,dried over MgSO₄, and concentrated to an oil in vacuo which was purifiedby flash column chromatography using 1:1 hex/ethyl acetate as eluent toyield a light yellow oil (4.00 g, 77%).

NMR: (CDCl₃) 1.06,t,3H; 1.85,m,2H; 3.13,t,2H; 3.74,t,2H; 3.91,s,3H;4.08,t,2H; 7.31,d,1H; 7.46,d,1H; 9.86,s,1H. M.S. (CI): 271 (100%).

Step B Preparation of2-(3-(2-hydroxyethylthio)-5-methoxy-4-propoxyphenyl)-1,3-dioxalane (53)(FIG. 24)

3-(2-hydroxyethylthio)-5-methoxy-4-propoxybenzaldehyde (52) (FIG. 24)(0.738 g,2.73 mmole), ethylene glycol (0.678 g,10.92 mmole), PPTS (0.274g, 1.09 mmole) and 40 ml dry benzene were refluxed with Dean-Starkremoval of the benzene-water azeotrope for 5 hours. The benzene wasremoved in vacuo and the remaing oil redissolved in CH₂ Cl₂ which waswashed with 10% NaHCO₃, H₂ O and dried over sodium sulfate. The solventwas removed in vacuo and the oil purified by flash column chromatographyusing 2:1 hex/ethyl acetate as eluent to yield a light tan oil (0.616 g,71%).

NMR: (CDCl₃) 1.03,t,3H; 1.84,m,2H; 3.05,t,2H; 3.66,t,2H; 3.85,s,3H;3.95,t,2H; 4.07,m,4H; 5.71,s,1H; 6.93,d,1H; 7.08,d, 1H.

Step C Preparation of3-(2-hydroxyethylsulfonyl)-5-methoxy-4-propoxybenzaldehyde (54) (FIG.24)

2-(3-(2-hydroxyethylthio)-5-methoxy-4-propoxyphenyl)-1,3-dioxalane (53)(FIG. 24) (2.11 g,6.70 mmole) was dissolved in 15 ml CH₂ Cl₂ and wascooled to 0° C. under an N₂ - atmosphere. To this solution was slowlyadded 80% MCPBA (3.32 g,15.41 mmole) along with an additional 10 ml CH₂Cl₂. The reaction was allowed to warm to room temperature over a 6 hourperiod. The m-chloro-benzoic acid precipitate was removed by suctionfiltration end the filtrate was washed with 10% NaHCO₃ and H₂ O. Theorganic layer was then added to 20 ml 10% HCl and the mixture wasstirred vigorously overnight. The organic layer was separated, driedover MgSO₄, and evaporated to an impure white solid which was purifiedby flash column chromatography using 2:1 hexane/ethyl acetate as eluentto yield a white solid (1.20 g, 60%).

NMR: (CDCl₃) 1.03,t,3H; 1.88,m,2H; 2.70,br s,1H; 3.65,t,2H; 3.96,s,3H;3.98,t,2H; 4.24,t,2H; 7.68,d,1H; 7.80,d,1H; 9.93,s,1H. M.S. (IBu) 302(100%). Melting Point 111°-112° C. Anal. calcd. for C₁₃ H₁₈ O₆ S: C,51.64; H, 6.00; S,10.60. Found: C, 51.67; H,5.99; S, 10.52.

Step D Preparation ofcis/trans2-(3-(2-hydroxyethylsulfonyl)-5-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(22) (FIG. 25)

1-(3-(2-hydroxyethylsulfonyl)-5-methoxy-4-propoxybenzaldehyde (54) (FIG.24) (0.88 g,2.91 mmole), 1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol(39) (FIG. 19) (0.947 g, 3.64 mmole) and 0.365 g of pyridiniumpara-toluene sulfonate was added to 120 ml dry benzene and refluxed withDean-Stark removal of the benzene- water azeotrope for 24 hours. Thebenzene was removed in vacuo, and the remaining oil redissolved indichloromethane. The organic layer was washed with 10% NaHCO₃ and H₂ O.The organic layer was dried over MgSO₄, and evaporated in vacuo to anoil which was purified by flash column chromatography with 1:1 hex/ethylacetate as eluent. The product mixture (white foam) contains a 1.0/1.0cis/trans ratio (1.254 g, 79%).

trans/cis epimers:

NMR: (CDCl₃) 1.04,t,6H; 1.87,m,4H; 3.45-3.60,m,4H; 3.64,t,4H;3.92,s,12H; 3.95,s,6H; 3.97,t,4H; 4.12,t,4H; 4.88,dd,1H; 5.07,dd,1H;5.53,s,2H; 5.74,s,1H; 5.82,s,1H; 6.73,s,2H; 6.76,s,2H; 7.41,d, 1H;7.43,d,1H; 7.71,d, 1H; 7.80,d,1H. M.S. (IBu): 544 (100%) Melting Point56°-60° C. Anal. calcd. for C₂₄ H₃₂ O₈ S₃ : C, 52.92; H, 5.92; S,17.66.Found C, 52.72; H,5,89; S, 17.53.

EXAMPLE 33 Preparation ofcis/trans-2-(3-(vinylsufonyl)-5-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(23) (FIG. 25)

1:1cis/trans-2-(3-(2-hydroxyethylsulfonyl)-5-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(22) (FIG. 25) (0.30 g,0.55 mmole), pyridine (90 μl) and 15 ml drychloroform was stirred under an argon atmosphere. To this solution wasadded methane sulfonyl bromide (0.108 g,0.679 mmole) predissolved in 1ml dry chloroform. The reaction was stirred at room temperature for 4hours. TLC shows no change, however, the solvent is removed in vacuo andthe remaining oil added to a flash silica column using 2:1 hex/ethylacetate as eluent. The vinyl sulfone compound is formed on the columnand only one product eludes off the column. The product mixture (foam)contains a 1.0/1.0 cis/trans ratio (0.236 g, 82%).

cis/trans epimers:

NMR: (CDCl₃) 1.03,t,6H; 1.86,m,4H; 3.45-3.70,m,4H; 3.84,s,6H;3.88,s,12H; 3.89,s,3H; 3.92,s,3H; 4.12,t,4H; 4.87,dd,1H; 5.07,dd,1H;5.73,s,1H; 5.82,s,1H; 6.05,d,2H; 6.42,d,1H; 6.49,d,1H; 6.72,s,2H;6.75,s,2H; 7.00,dd,2H; 7.38,d,1H; 7.40,d,1H; 7.71,d,1H; 7.80,d,1H. M.S.(CI): 527 (100%) 227, 195.

EXAMPLE 34 Preparation ofcis/trans-2-(3-(2-N,N-dimethylaminoethylsulfonyl)-4-propoxy-5-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(24) (FIG. 25)

2-(3-(vinylsufonyl)-5-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(22) (FIG. 25) (0.035 g,0.0821 mmole) was dissolved in absolute ethanol(5 ml) which was cooled to 0° C. under an argon atmosphere.Dimethylamine gas was then condensed into the reaction until 10 drops ofamine were added. The reaction was stirred at 0° C. for 3 hours. Thesolvent and excess amine were removed in vacuo, and the remaining oilpurified by flash column chromatography with 1:1 hex/ethyl acetate aseluent. The product mixture (oil) contains a 1.0/1.0 cis/trans ratio(0.036 g, 78%).

cis/trans epimer:

NMR: (CDCl₃) 1.03,t,6H; 1.86,m,4H; 2.21,s,12H; 2.74,dt,4H;3.45-3.70,m,4H; 3.63,t,4H; 3.83,s,6H; 3.87,s,12H; 3.90,s,3H; 3.93,s,3H;4.11,t,4H; 4.88,dd,1H; 5.07,dd.1H; 5.73,1H; 5.81,s,1H; 6.71,s,2H;6.74,s,2H; 7.39,d,1H; 7.41,d,1H; 7.66,d,1H; 7.75,d,1H. M.S. (CI):572,389, 346, 330, 227, 195 (100%).

EXAMPLE 35 Preparation ofcis/trans-2-(3-(2-N,N-diethylaminoethylsulfonyl)-4-propoxy-5-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1-3-dithiolane(25) (FIG. 25)

2-(3-(vinylsulfonyl)-5-methoxy-4-propoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(22) (FIG. 25) (0.015 g,0.076 mmole) was dissolved in absolute ethanol(10 ml) and diethylamine (2 drops) was into the reaction which wasstirred at room temperature for 24 hours. The solvent and excess aminewere removed in vacuo, and the remaining oil purified by flash columnchromatography with 1:1 hex/ethyl acetate as eluent. The product mixture(oil) contains a 1.0/1.0 cis/trans ratio (0.0049 g, 29%).

cis/trans epimer:

NMR: (CDCl₃) 0.94,dt,6H; 1.04,t,6H; 1.86,m,4H; 2.43,dq,6H; 2.92,dt,4H;3.45-3.70,m,4H; 3.63,t,4H; 3.83,s,6H; 3.87,s,12H; 3.90,s,3H; 3.93,s,3H;4.11,t,4H; 4.87,dd,1H; 5.07,dd,1H; 5.73,1H; 5.82,s,1H; 6.72,s,2H;6.75,s,2H; 7.38,d,1H; 7.40,d,1H; 7.68,d,1H; 7.76,d,1H. M.S. (CI) 600,402,374,358,227, 195, 100 (100%).

EXAMPLE 36 Preparation ofcis/trans-2-(3-(2-morpholinoethylsulfonyl)-4-propoxy-5-methoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(26) (FIG. 25):

2-(3-(vinylsufonyl)-5-methoxy-4-propoxyphenyl)-4-(3,4,5-methoxyphenyl)-1,3-dithiolane(22) (FIG. 25) (0.040 g,0.076 mmole) was dissolved in absolute ethanol(10 ml) and morpholine (13 ml) was into the reaction which was stirredat room temperature for 4 hours. The solvent and excess amine wereremoved in vacuo, and the remaining oil purified by flash columnchromatography with 1:1 hex/ethyl acetate as eluent. The product mixture(oil) contains a 1.0/1.0 cis/trans ratio (0.022.5 g, 49%).

Cis/trans epimers:

NMR: (CDCl₃) 1.03,t,6H; 1.86,m,4H; 2.31,t,8H; 2.74,dt,4H; 3.39,t,8H;3.45-3.70,m,4H; 3.84,s,6H; 3.88,s,12H; 3.91,s,3H; 3.93,s,3H; 4.11,t,4H;4.86,dd,1H; 5.07,dd,1H; 5.73,1H; 5.82,s,1H; 6.71,s,2H; 6.75,s,2H;7.38,d,1H; 7.40,d,1H; 7.68,d,1H; 7.76,d,1H. M.S. (CI) 614, 372, 195(100%).

EXAMPLE 37Trans-2-(3,5-dimethoxy-4-(2'-hydroxyethoxy)phenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(27) (FIG. 26)

Step A Preparation of 3,5-dimethoxy-4-(2'-hydroxyethoxy)benzaldehyde(55)

Syringaldehyde (1.0 g,5.49 mmole), 2-iodo-1-ethanol (1.90 g,10.98 mmole)and potassium carbonate (1.90 g, 13.77 mmole) were added to 15 ml dryDMF and stirred for 24 hours at 80° C. under an argon atmosphere. Thereaction mixture was added to 100 ml H₂ O and acidified with 10% HCl.The product was extracted into CHCl₃, dried over MgSO₄, and concentratedto an oil in vacuo. The remaining oil was purified by flash columnchromatography using 1:1 hex/ethyl acetate as eluent (1.009 g, 81%).NMR: (CDCl₃) 3.23,t,1H; 3.73,m,2H; 3.93,s,6H; 4.20,t,2H; 7.13,s,2H;9.87,s,1H M.S. (CI): 227 (100%).

Step B Preparation oftrans-2-(3,5-dimethoxy-4-(2'-hydroxyethoxy))-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(27) (FIG. 26)

3,5-dimethoxy-4-(2-hydroxyethoxy)benzaldehyde (55) (2.14 g,9.47 mmole),1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (2.54 g,9.77mmole) and 1.00 g of pyridinium para-toluene sulfonate was added to 75ml dry benzene and refluxed with Dean-Stark removal of the benzene-waterazeotrope for 24 hours. The benzene was removed in vacuo, end theremaining oil redissolved in ethyl acetate. The organic layer was washedwith 10% HCl and H₂ O. The organic layer was dried over MgSO₄, filtered,and evaporated in vacuo to an oil which was purified by flash columnchromatography with 12 hex/ethyl acetate as eluent. The product mixture(white foam) titurates to a solid in diethylether (3.10 g,70%). Thetrans isomer was isolated after three recrystallizations from CH₂ Cl₂/hexane (1.00 g).

Trans epimer:

NMR: (CDCl₃) 3.40,t,1H; 3.48,dd,1H; 3.64,dd,; 3.72,m,2H; 3.84,s,3H;3.88,s,6H; 3.90,s,6H; 4.13,t,2H; 5.06,dd,1H; 5.83,s,1H; 6.72,s,2H;6.85,s,2H. M.S. (CI): 469 (100%). Melting point 121°-122° C. Anal.calcd. for C₂₂ H₂₈ O₇ S₂ : C, 56.39; H, 6.02; S,13.68. Found: C, 56.45;H,6.05; S, 13.62.

EXAMPLE 38 Preparation oftrans-2-(3,5-dimethoxy-4-(2'-acetoxyethoxy)phenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(28) (FIG. 26)

Trans-2-(3,5-dimethoxy-4-(2'-hydroxyethoxyphenyl))-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(27) (FIG. 26) (0.05 g,0.107 mmole) was dissolved in 5 ml dry chloroformand 20 μl of pyridine was added. The reaction was cooled to 0° C. underan argon atmosphere and 10 μl of acetyl chloride was added. The reactionwas allowed to warm to room temperature and stir for 2 hours. Thereaction was quenched with 10% HCl and extracted with chloroform. Theorganic layer was washed with H₂ O, dried over MgSO₄ and concentrated toa yellow oil which was purified by flash column chromatography using 2:1hexane/ethyl acetate as eluent. The column yields 34 mg of the desiredacetate as a white foam (63% yield).

Trans epimer:

NMR: (CDCl₃) 2.07,s,3H; 3.46,dd,1H; 3.48,dd,1H; 3.63,dd,1H; 3.83,s,3H;3.86,s,6H; 3.87,s,6H; 4.18,t,2H; 4.33,t,2H; 5.05,dd,1H; 5.80,s,1H;6.71,s,2H; 6.81,s,2H. M.S. (CI): 540, 298, 195 (100%).

EXAMPLE 39N'-hydroxyl-N'-methyl-N-[2,3-dimethoxy-5-{3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl}]benzylurea (29) (table 1)

Step A Preparation of 2-(5-cyano-3,4-dimethoxyphenyl)-1,3-dioxolane (50)(FIG. 22)

2-(3,4-dimethoxy-5-iodophenyl)-1,3-dioxolane (42) (FIG. 22) (2.80 g, 8.0mmole), copper cyanide (5.7 g, 32.0 mmole) and dry DMF (50 ml) werestirred under an argon atmosphere for 24 hours at 140° C. The reactionwas cooled to room temperature, filtered through celite, and thefiltrate concentrated to an oil in vacuo. The dark brown oil waspurified through a short flash silica column using 2:1 hexane/ethylacetate as eluent to yield 1.471 g (74%) of a white solid. The productcan be recrystallized from hexane/ethyl acetate.

NMR: (CDCl₃) 1.46,d,1H; 2.21,m, 1H; 3.90,s,3H; 3.97,m,2H; 4.00,s,3H;4.26,dd,2H; 5.43,s,1H7.25,brs,2H. M.S. (CI) 250 (100%). Melting point76.5°-77.5° C. Anal. calcd. for C₁₃ H₁₅ O₄ N: C, 62.64: H, 6.06; N,5.62.Found: C, 62.45; H,6.02; N, 5.59.

Step B Preparation of2-(5-aminomethyl-3,4-dimethoxyphenyl)-1,3-dioxolane (51) (FIG. 22)

2-(5-cyano-3,4-dimethoxyphenyl)-1,3-dioxolane (50) (FIG. 22) (0.555 g,2.23 mmole) was predissolved in 2 ml dry THF and 10 ml anhydrous diethylether. To this solution under an argon atmosphere at room temperaturewas added 2.23 ml of 1.0M lithium aluminum hydride in diethyl ethersolution. The reaction was then stirred at room temperature for 4 hours.The reaction was then cooled to 0° C. and the excess hydride destroyedwith H₂ O. The reaction mixture was subsequently quenched with 10% NaOHand extracted with diethyl ether. The organic layer was dried overMgSO₄, and concentrated to an oil in vacuo.

NMR: (CDCl₃) 1.47,d, 1H; 2.18,m,1H; 3.77,bd,2H; 3.79,s,3H; 3.85,s,3H;3.94,dt,2H; 4.21,dd,2H; 5.40,s,1H; 6.95,bs,2H.

Step C Preparation ofN'-hydroxyl-N'-methyl-N-[2,3-dimethoxy-5-formylbenzyl urea (55)

2-(5-aminomethyl-3,4-dimethoxyphenyl)-1,3-dioxolane (51) isolated fromthe reduction 2-(5-cyano-3,4-dimethoxyphenyl)-1,3-dioxolane 50 (0.400 g,2.23 mmole) as in step B was dissolved in 10 ml dichloromethane andtriethylamine (202 mg). To this solution was added triphosgene (190 mg,0.642 mmole) and the reaction was refluxed under nitrogen overnight. Thereaction was cooled to room temperature and methyl hydroxylaminehydrochloride (403 mg, 4.83 mmole) predissolved in THF (10 ml), H₂ O (1ml) and triethylamine (488 mg) was added. The reaction was stirred atroom temperature for two hours and was then quenched and extracted with10 ml 5% HCl. The organic layer was separated and then stirredvigorously overnight over an equivolume of 10% HCl. The organic layerwas separated, dried over MgSO₄, and concentrated to a brown oil invacuo which was purified by flash column chromatograpy using 1:1hexane/ethyl acetate-100% NMR: (CHCl₃) 3.15,s,3H; 3.91.s,3H; 3.96,s,3H;4.45,s,2H; 6.41,br s,1H; 7.36,d,1H; 7.41,d,1H; 9.83,s,1H. M.S. (Cl):537, 269, 99 (100%)

Step D: Preparation ofN'-hydroxyl-N'-methyl-N-[2,3-dimethoxy-5-[3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl)]benzylurea (29):

2-(5-aminomethyl-3,4-dimethoxyphenyl)-1,3-dioxolane (55) can be cyclizedusing the standard procedure illustrated in FIG. 1 to form dithiolane29.

EXAMPLE 40 Preparation of2-(3,4-dimethoxy-5-methyl-N,N-dimethylaminophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(30) (table 1)

2-(5-aminomethyl-3,4-dimethoxyphenyl)-1,3-dioxolane (51) (FIG. 22) canbe reductively methylated following the procedure given in example 15,the acetal hydrolyzed following the procedure given in example 28,stepC, and the resulting aldehyde cyclized using the standard procedureillustrated in FIG. 19 to form diothiolane (30) (Table 1).

EXAMPLE 41 Preparation oftrans-2-[{2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl)phenoxy}ethoxycarbonylaminomethyl]pyridine(31) (FIG. 26)

Trans-2-(3,5-dimethoxy-4-(2'-hydroxyethoxyphenyl))-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(27) (FIG. 26) (0.395 g,0.844 mmole) was dissolved in 25 ml drychloroform and 136 μl of pyridine was added. The reaction was cooled to0° C. under an argon atmosphere and 116 μl of chlorophenylcarbonate wasadded. The reaction was allowed to warm to room temperature and wasstirred for 2 hours. The reaction was quenched with 5% HCl and extractedwith chloroform. The organic layer was dried over MgSO₄ and concentratedto 25 ml total volume. 2-(aminomethyl)pyridine (108 ml, 1.05 mmole) wasadded and the reaction was refluxed under an argon atmosphere for 12hours. The reaction was concentrated to 1 ml total volume and purifiedby flash column chromatography using 1/1 hexane/ethyl acetate-100% ethylacetate as eluent. The column yields 365 mg (72%) as a white foam.

Trans epimer:

NMR: (CDCl₃) 3.46,dd,1H; 3.64,dd,1H; 3.81,s,6H; 3.84,s,3H; 3.88,s,6H;4.16,t,2H; 4.45,t,2H; 4.62,d,2H; 5.05,dd,1H; 5.07,s,2H; 5.82,s,1H;6.72,s,2H; 6.81,s,2H; 7.15,m,2H; 7.61,t,1H; 8.50,d,1H. M.S. (CI): 603(100%) 195.

EXAMPLE 42 Preparation oftrans-2-[N-acetyl[{2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl)phenoxy}ethoxycarbonyl]aminomethyl]pyridine(32) (FIG. 26)

Trans-2-[{2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl)phenoxy}ethoxycarbonylaminomethyl]pyridine(31) (FIG. 26) (0.313 g,0.520 mmole) was dissolved in 20 ml drydichloromethane. The reaction was cooled to 0° C. under an argonatmosphere and 44 μl of acetyl chloride was added. The reaction wasallowed to warm to room temperature and was stirred overnight. Thereaction was recooled to 0° C. and 87 μl triethyl amine and 44 μl acetylchloride was added. The reaction was then allowed to warm to roomtemperature and was stirred for an additional 12 hours. The reaction wasthen quenched with 10% NaHCO₃ and extracted with dichloromethane. Theorganic layer was dried over MgSO₄ and concentrated to a brown oil whichwas purified by flash column chromatography using 1:1 hexane/ethylacetate--1:2 hexane/ethyl acetate as eluent. The column yields 293 mg(88%) as a white foam.

Trans epimer:

NMR: (CDCl₃) 2.63,s,3H; 3.47,dd,1H; 3.48,dd.1H; 3.64,dd,1H; 3.84,s,6H;3.86,s,3H; 3.88,s,6H; 4.18,t,2H; 4.35,t,2H; 4.62,d,2H; 5.05,dd,1H;5.81,s,1H; 6.72,s,2H; 6.81,s,2H; 7.38,t,1H; 7.51,d,1H; 7.88,t,1H;8.56,d,1H. M.S. (CI): 644, 403, 195, 133, 84 (100%).

EXAMPLE 43 Preparation oftrans-2-[N-acetyl[{2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl)phenoxy}ethoxycarbonyl]aminomethyl]-1-ethylpyridinium triflate (33) (FIG. 26)

2-[-N-acetyl[{2,6-dimethoxy-4-(3-(3,4,5-trimethoxyphenyl)-2,4-dithiolanyl)phenoxy}ethoxycarbonyl]aminomethyl]pyridine(32) (FIG. 26) (0.049 g, 0.076 mmole), diisopropylethylamine (8 μl,0.076 mmole) and 5 ml anhydrous dichloromethane were cooled to 0° C.under a nitrogen atmosphere. Ethyl triflate (10 μl, 0.076 mmole) wasadded. The reaction was allowed to warm to room temperature and wasstirred for 12 hours. The solvent was removed in vacuo and the remainingresidue redissolved in 0.5 ml acetone. The acetone solution was purifiedby flash column chromatography using 100% ethyl acetate-10/1CHCl₃MeOH-4/1CHCl₃ /MeOH as eluent. The product was isolated as a 1.6/1.0trans/cis mixture of diastereomers as a white foam (0.047 g. 75%).

Cis/trans epimers:

NMR: (Acetone-D₆) 1.72,t,6H; 2.64,s,6H; 3.51-3.7,m,4H; 3.79,brs,12H;3.80,brs,18H; 4.12,m,4H; 4.45,m,4H; 4.96,m,7H; 5.17,dd,1H; 5.53,brs,4H;5.79,s,1H; 5.92,s,1H; 6.86,s,2H; 6.90,s,2H; 6.94,s,2H; 6.97,s,2H;8.08,brd,4H; 8.56,t,2H; 9.12,brd,2H.

EXAMPLE 44 Trans-bis-glutaric-amide dithiolane dimer (34a) andtrans-bis-pimelic-amide dithiolane dimer (34b) (see Table 3 and FIG.27).

Step A Preparation of trans-glutaric amide/acid dithiolane (56) (FIG.27)

Trans-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 27) (0.100 g,0.236 mmole) was predissolved in 10 ml drydichloromethane and was cooled to 0° C. under an argon atmosphere. Tothis solution was added 35 mg of diglutaric anhydride (0.035, 0.306mmole), and 1 drop of glacial acetic acid. The reaction was allowed towarm to room temperature and was stirred overnight. The solvent wasremoved in vacuo and the remaining residue purified by flash columnchromatography using chloroform--2:1 chloroform/methanol as eluent. Thecolumn yields 106 mg (84%) of a pale red foam.

Trans epimer:

NMR: (CDCl₃) 2.08,t,2H; 2.52,t,4H; 3.45,dd,1H; 3.65,dd,1H; 3.83,s,3H;3.87,s,3H; 3.88,s,6H.; 3.90,s,3H; 5.08,dd,1H; 5.81,s,1H; 6.72,s,2H;6.95,d,1H; 7.86,s,1H; 8.26,s,1H. M.S. (CI): 538, 89 (100%).

Step B Preparation of trans-bis-glutaric-amide dithiolane dimer (34a)(FIG. 27)

Compound (56) (FIG. 27) (0.038 g, 0.071 mmole),trans-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 27) (0.032 g,0.076 mmole). 2-chloro-1-methylpyridinium iodide(0.022 g, 0.085 mmole), triethylamine (0.014 g, 0.014 mmole) and drydichloromethane (5 ml) were refluxed under an argon atmosphereovernight. The reaction was quenched with 5% HCl and the productextracted into dichloromethane. The organic layer was dried overmagnesium sulfate and concentrated in vacuo to an oil which was purifiedby flash column chromatography using 1:1 hexane/ethyl acetate--100%ethyl acetate as eluent. The column yields 18 mg (27%) of a clear oil.

Trans epimer:

NMR: (CDCl₃) 2.09,m,2H; 2.80,t,4H; 3.43,dd,2H; 3.60,dd,2H; 3.76,s,6H;3.82,s,6H; 3.86,s,12H; 3.90,s,6H; 4.97,dd,2H; 5.78,s,2H; 6.70,s,4H;6.88,d,2H; 7.72,d,2H.

Preparation of trans-bis-pimelic-amide dithiolane dimer (34b) (FIG. 27)

Pimelic acid (0.0095 g, 0.059 mmole),trans-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 27) (0.05 g,0.118 mmole), 2-chloro-1-methylpyridinium iodide(0.036 g, 0.142 mmole), tri-n-butylamine (0.052 g, 0.284 mmole) and drytoluene (10 ml) were refluxed under an argon atmosphere for 5 hours. Thesolvent was removed in vacuo and the remaining residue was redissolvedin chloroform. The solution was washed with 5% HCl and H₂ O, dried overmagnesium sulfate and concentrated in vacuo to an oil which was purifiedby flash column chromatography using 1:1 hexane/ethyl acetate-1:2hexane/ethyl acetate as eluent. The column yields 26 mg (46%) of a clearoil.

Trans epimer:

NMR: (CDCl₃) 1.49,m,2H; 1.79,m,4H; 2.42,t,4H; 3.43,dd,2H; 3.65,dd,2H;3.83,s,6H; 3.86,s,6H;. 3.87,s,12H; 3.90,s,6H; 5.07,dd,2H; 5.81,s,2H;6.72,s,4H; 6.94,d,2H; 7.79,d,2H; 8.27,s,2H.

Following substantially the same procedure as described for compound 34b(FIG. 29), dimer 34c (FIG. 29) can be prepared.

EXAMPLE 45

Trans-bis-glycolic-amide dithiolane dimer (35a) (See FIGS. 27 and 28)

Step A Preparation of trans-glycolic amid/acid dithiolane (57) (FIG. 27)

Trans-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 27) (0.100 g,0.236 mmole) was predissolved in 10 ml drydichloromethane and was cooled to 0° C. under an argon atmosphere. Tothis solution was added 36 mg of 90% diglycolic anhydride (0.036, 0.283mmole). The reaction was allowed to warm to room temperature and wasstirred for 12 hours. The solvent was removed in vacuo and the remainingresidue purified by flash column chromatography using chloroform--3:1chloroform/methanol as eluent. The column yields 126 mg (99%) of a palered foam. The product will crystallize to a white solid fromhexane/ethyl acetate.

Trans epimer:

NMR: (CDCl₃) 3.45,dd,1H; 3.63,dd,1H; 3.83,s,3H; 3.86,s,3H; 3.87,s,6H;3.90,s,3H; 4.23,s,2H; 4.28.s,2H; 5.07,dd,1H; 5.65,bs,1H; 5.82,s,1H;6.72,s,2H; 7.00,d,1H; 8.22.s,1H; 9.08,s,1H. M.S. (CI): 539, 117 (100%).

Step B Preparation of trans-bis-glycolic-amide dithiolane dimer (35a)(FIG. 27)

Compound (57) (0.126 g, 0.234 mmole),Trans-2-(5-amino-3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(3) (FIG. 27) (0.099 g,0.234 mmole), 2-chloro-1-methylpyridinium iodide(0.072 g, 0.281 mmole), triethylamine (0.028 g, 0.281 mmole) and drydichloromethane (10 ml) were refluxed under an argon atmosphere for 15hours. The reaction was quenched with 5% HCl and the product extractedinto dichloromethane. The organic layer was dried over magnesium sulfateand concentrated in vacuo to an oil which was purified by flash columnchromatography using 1:1 hexane/ethyl acetate-100% ethyl acetate aseluent. The column yields 101 mg (46%) of a clear oil which crystallizedfrom ethyl acetate/hexane.

Trans epimer:

NMR: (CDCl₃) 3.46,dd,2H; 3.65,dd,2H; 3.84,s,6H; 3.86,s,6H; 3.88,s,12H;3.91,s,6H; 4.28,s,4H; 5.08,dd,1H; 5.83,s,2H; 6.72,s,4H; 7.01,d,2H;8.26,d,2H; 8.85,bs,2H. M.S. (IBu): 945, 195 (100%).

Following substantially the same procedure as described for compound 34,dimers 35b and 35c can be prepared.

EXAMPLE 46 Trans-bis-alkyl-amine dithiolane dimers (36a,b,c) (See FIG.29)

Dimers of type 36a, b, and c (FIG. 29) can be readily synthesizedstarting withtrans-2-(3,4-dimethoxy-5-methylaminophenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(4) (table 1). and alkyl dihalides or p-ditosylates such as thecommercially available 1,3-propanediol-p-ditosylate, using conditions asreported by Erez et al., in J. Med. Chem., 25, 847-849 (1982).

EXAMPLE 472-(3,5-dimethoxy-4-hydroxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolanetetraethyleneglycol dimer (Compound 22a)

Tetraethyleneglycol-1,10-diiodide (0.125 g, 0.302 mmole),2-(3,5-dimethoxy-4-hydroxyphenyl)-4-(3,4,5-trimethoxyphenyl)-1,3-dithiolane(compound 5 on FIG. 2) (0.270 g, 0.637 mmole), potassium tert-butoxide(0.071 g, 0.637 mmole) and 5 ml dry THF are stirred at room temperaturefor 24 hours. Dry DMF (1 ml) is added and the reaction is stirred for anadditional 12 hours. The solvent is removed in vacuo and the remainingoil is purified to a white foam by flash column chromatography using2:1-1:2 hex/ethyl acetate as eluent (0.174 g). C,H Analysis: C(57.24,57.21), H (6.20,6.17). Following substantially the sameprocedures, the other dimeric 2,4-diaryl-1,3-dithiolane compounds (i.e.,compounds 22B-G) reported in FIGS. 6a and 6b are prepared.

As discussed above, another series of neolignan derivatives which arepotent PAF antagonist compounds can be isolated from the leaves of thePiper futokadsura (Chinese herbal plant). FIG. 7 shows sevaral compoundscompounds isolated from Piper futokadsura via extraction. In particular,the plant material is soaked for three days in dicloromethane thenfiltered using a Buchner funnel and water aspiration. The resultingfiltrate is concentrated in vacuo and futoquinol, kadsurenone, futoxide,and futoenone are separated by flash chromotography on silica gel usinga gradient of hexane and ethyl acetate. Shen et al. in Proc. Natl. Acad.Sci. (U.S.A.), 82. 672-678 (1985), reported that kadsurenone is apotent, specific and competitive inhibitor of PAF an the receptor level.A part of this invention is particularly concerned with futoenone andderivatives thereof. Futoenone is a major component of Piperfutokadsura, constituting 0.1% dry weight of the plant. While thestructure and several syntheses of futoenone have previously beenpublished (see, Ogiso et al., Tet. lett., 16, 2003 (1968) and Ogiso etal., Chem. Pharm. Bull., 18, 1005 (1970)), the inventors are the firstto observe that futoenone posesses PAF antagonist activity. Using theprocedures described above for the human platelet assay in PRP,futoenone was found to have an IC₅₀ value of approximately 13.6 μM forplatelet aggregation induced by 0.1 μM PAF (see FIG. 14b where X═O andR₁,R₂ =a single --CH₂ -- which closes the ring between the oxygens).

Many futoenone derivative compounds have been prepared and the PAF and5-lipoxygenase activity for several of the compounds have beendetermined. FIGS. 8a and 8b show the numbering scheme used to identifythese new compounds and FIGS. 9-13 schematically show the syntheticroutes used to prepare the new compounds. The following Examples relateparticularly to FIGS. 9-13 where the compound number used in an Examplerelates to the number identified in FIGS. 9-13.

EXAMPLE 482-[3-acetyl-2-(1,3-benzodioxol-5-yl)butane]-7-acetyl-6-methoxydihydrobenzofuran(103, FIG. 9)

Boron trifluoride etherate (0.231 ml, 0.0014 mols) is added to a stirredsolution of futoenone (101) (1.0 g, 0.0029 mols) in acetic anhydride(16.76 ml). The reaction is monitored with thin layer chromatography(TLC) until no starting material is observed. This involves stirring atroom temperature for nine hours then gently warming for 30 minutes. Thecolor changes from yellow to orange over the course of the reaction. Thereaction mixture is poured over ice-water and extracted with ether. Theether extract is washed with sodium bicarbonate followed by water anddried over magnesium sulfate. The extract is filtered and dried invacuo. The reaction mixture is purified by flash chromatography on asilica gel (4.0 g with 5:1 hexane-ethyl acetate as the eluant). Thefractions corresponding to the product, as determined by ¹ H NMR spectraare combined and concentrated in vacuo affording a bright yellow foam;0.87 mg (66%).

¹ H NMR ppm: 1.05 (3H, d), 1.76 (1H, m), 2.06 (3H, s) 2.23 (1H, m), 2.28(3H, s), 2.71 (1H,d) 2.98 (1H, m) 3.07 (1H, dd), 3.74 (3H, s), 4.43 (1H,m), 5.02 (1H, m), 5.94 (2H, s), 6.47 (1H, s), 6.72 (4H, m). M+(CI)=442(Mass Spec. parent ion peak).

EXAMPLE 492-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-7-hydroxy-6-methoxydihydrobenzofuran(105, FIG. 9)

Acetyl chloride (0.77 ml, 1.08 mmoles) in methanol (methanolic HClprepared by addition of acetyl chloride to dry methanol at 0° C.) isadded to a stirred solution of2-[3-acetyl-2-(1,3-benzodioxol-5-yl)butane]-7-acetyl-6-methoxydihydrofuran(103, prepared as described in Example 48) (1.45 g, 3.3 mmoles) inchloroform (5 ml, 6.2 mmoles). The reaction turns orange-red with theaddition of methanolic HCl. The reaction is stirred at room temperaturefor six hours and is monitored by TLC every hour. The reaction mixtureis treated with sodium bicarbonate, diluted with 30 ml of chloroform,and washed with water. The extract is dried over sodium sulfate,filtered, and concentrated in vacuo. The extract shows three spots onTLC (1:1 hexane-ethyl acetate) with the product being the most polar ofthe three. The reaction is purified by flash chromatography on silicagel (1:1:2 hexane-ether-dichloromethane as the eluant). The fractionscorresponding to the product are combined and concentrated (0.84 g,2.4×10-3 mmoles,71%) and resemble a pale yellow foam.

Anal. Calcd. for C₂₀ H₂₂ O₆ : C, 67.03; H, 6.19. Found: C, 66.88; H,6.26 (Analytic data C=carbon, H=hydrogen). ¹ H NMR ppm: 1.07 (3H, d),1.92 (1H, m), 2.4 (1H, m), 2.68 (1H, dd), 2.84 (1H, m), 3.07 (1H, dd),3.78 (3H, s), 3.93 (1H, m), 4.5 (1H, m), 5.5 (1H, s), 5.95 (2H, s), 6.4(1H, s), 6.63 (4H, m). M+(CI)=358.

EXAMPLE 502-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-7-allyloxy-6-methoxydihydrobenzofuran(107, FIG. 9)

Potassium carbonate (0.97 g, 7.02 mmoles), 18-Crown-6 ether (0.25 g,9.45 mmoles) and allyl bromide (0.32 Ml, 3.7 mmoles) are added to astirred solution of2-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-7-hydroxy-6-methoxydihydrobenzofuran(105, prepared as described in Example 49) (0.84 g, 2.35 mmoles) in THF(12 ml). The reaction is stirred for one hour and is monitored by TLC.After four hours, allyl bromide (0.5 eq) is added to drive the reactionto completion. The reaction is stirred for an additional two hours withno change. Another 0.5 eq of allyl bromide is then added to reaction.After stirring a total of 6.5 hours, the reaction was warmed for 0.5 h.The reaction mixture is poured over ice-water, extracted with methylenechloride, and the extract is dried with sodium sulfate. The reactionmixture is purified by flash chromatography on a silica gel (150 g with1:1:1 hexane-diethyl ether-dichloromethane as the eluant). The fractionsidentified by TLC corresponding to the allyl ether are combined, andconcentrated in vacuo producing a foam, 0.76 g (1.91×10-3 mmoles 82%). ¹H NMR ppm: 1.07 (3H ,d), 1.85 (1H, m), 2.41 (1H, m), 2.72 (1H, m), 3.09(1H, dd), 3.78 (3H, s), 3.85 (1H, m), 4.32 (1H, m), 4.55 (2H, d), 5.34(2H, dd), 5.94 (2H, s), 6.04 (1H, m), 6.4 (1H, s), 6.72 (4H, m).M+(CI)=398.

EXAMPLE 51 2-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-8-allyl-7-hydroxy-6-methoxydihydrobenzofuran (108a, FIG. 9)

N,N-diethylaniline (2.5 ml) is added to 0.8 g of2-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-7-allyloxy-6-methoxydihydrobenzofuran(107, prepared according to Example 50). The stirred solution is placedin an oil bath and heated at 190°-200° C. for three hours. The reactionis diluted with ether and washed with 10% HCl followed by water. Theether extract is dried over sodium sulfate overnight. The extract isfiltered and concentrated in vacuo. The reaction is purified by flashchromatography on silica gel (8.0 g with 1:1:1 hexane-diethylether-dichloromethane) to produce 0.043 g (40%)2-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-8-allyl-7-hydroxy-6-methoxydihydrobenzofuran(108a).

¹ H NMR ppm: 1.05 (3H, d), 1.82 (1H, m), 2.69 (1H, dd), 2.85 (1H, m),3.05 (1H, dd), 3.36 (2H, d), 3.79 (3H, s), 3.86 (1H, m), 4.53 (1H, m),5.04 (21H, dd), 5.61 (1H, s), 5.95 (2H, s), 6.01 (1H, m) 6.57 (1H, s),6.73 (3H, m).

EXAMPLE 522-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-8-allyl-6,7-dimethoxydihydrobenzofuran(108b, FIG. 9)

Potassium carbonate (8.7 mg, 0.063 mmoles), 18-crown-6 ether (6.7 mg,0.025 mmoles), and iodomethane (3.92 ml, mmoles) is added to a stirredsolution of2-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-8-allyl-7-hydroxy-6-methoxydihydrobenzofuran(108a, prepared according to Example 51) in THF (1 ml). The reaction isstirred at 0° C. for one hour and then is gradually warmed to roomtemperature. The reaction is monitored by TLC until little startingmaterial remains (approximately five hours elapsed time). The reactionmixture is poured over ice-water, extracted with dichloromethane, andwashed with 10% HCl followed by water. The extracts are dried oversodium sulfate and concentrated in vacuo. The reaction mixture ispurified by flash chromatography on silica gel (2.5 g with 2:1hexane-ethyl acetate as the eluant) to obtain 14.2 mg (53% yield) of2-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-8-allyl-6,7-dimethoxydihydrobenzofuran (108b). The product andstarting material run very close together on silica so separation isdifficult and several fractions may contain a mixture of methyl etherand starting material. M+(CI)=413 ¹ H NMR ppm: 1.06 (3H, D), 1.82 (1H,m), 2.69 (1H, dd), 2.85 (1H, m), 3.13 (1H, dd), 3.36 (2H, d), 3.79 (6H,s), 3.86 (1H, m), 4.53 (1H, m), 5.04 (2H, dd), 5.61 (1H, s), 5.95 (2H,s), 6.01 (1H, m), 6.57 (1H, s), 6.73 (3H, m).

EXAMPLE 53

Following substantially the same procedure as described in Example52,the following related compounds can be prepared:

2-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-8-allyl-7-allyloxy-6-methoxydihydrobenzofuran(108c, FIG. 9)

M+(CI)=440 ¹ H NMR ppm: 1.06 (3H, d), 1.82 (1H, m), 2.69 (1H, dd), 2.85(1H, m), 3.13 (1H, dd), 3.23 (2H, d), 3.79 (3H, s), 3.86 (1H, m), 4.53(1H, m), 5.04 (2H, dd), 5.95 (2H, s), 6.73 (4H, m).

2-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-7-acetyl-8-allyl-6-methoxydihydrobenzofuran(108d, FIG. 9)

M+(CI)=439 ¹ H NMR ppm: 1.06 (3H, d), 1.82 (3H, s), 2.69 (1H, dd), 2.85(1H, m), 3.13 (1H, dd), 3.36 (2H, d), 3.79 (3H, s), 4.42 (2H, d), 4.50(1H, m), 5.04 (2H, dd), 5.30 (2H, dd), 5.95 (2H, dd), 6.09 (2H, m), 6.61(1H, s), 6.73 (3H, m).

2-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-8-allyl-7-benzyloxy-6-methoxydihydrobenzofuran(108e, FIG. 9)

M+(CI)=489 ¹ H NMR ppm: 1.06 (3H, d), 1.82 (1H, m), 2.69 (1H, dd), 2.85(1H, m), 3.13 (1H, dd), 3.36 (2H, d), 3.79 (3H, s), 3.86 (1H, m), 4.53(1H, m), 4.95 (2H, d), 4.98 (2H, dd), 6.70 (4H, m), 7.24 (1H, s), 7.4(2H, m), 7.55 (2H, d).

EXAMPLE 54 4-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-hydroxy-5-methyl-8H-2,5a-methano-1-benzoxepin-8-one(109, FIG. 10)

Futoenone (50 mg, 0.15 mmol) and 30% sulfuric acid (7.5 ml) are added toa 25 ml round bottom flask. This mixture is heated with a heating mantleto reflux for approximately six hours. The reaction mixture is dilutedwith distilled water and crystals begin to precipitate. The flask isplaced in a refrigerator to aid in precipitation. The crystals arecollected by filtration, 300 mg (80%). M+(CI)=327. ¹ H NMR ppm: 0.59(3H, d), 1.25 (1H, s), 1.72 (1H, t), 2.03 (1H, m), 2.17 (1h, d), 2.35(2H, m), 2.53 (1H, m), 5.06 (1H, t), 5.72 (1H, s), 5.83 (1H, s), 5.93(2H, s), 6.69 (3H, m).

EXAMPLE 554-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-6-allyl-7-hydroxy-5-methyl-8H-2,5a-methano-1-benzoxepin-8-one(110, FIG. 10)

Potassium carbonate (172.7 mg, 1.25 mmol) and mesyl allyl ether (113 mg,0.83 mmol) are added to a stirred solution of4-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-hydroxy-5-methyl-8H-2,5a-methano-1-benzoxepin-8-one(109, as prepared in Example 54) in DMF (4 ml). The reaction is stirredat room temperature overnight, after which time TLC still showsunreacted starting material present. An additional 50 μl mesyl allylether is then added to the reaction and the reaction is then starred foranother 24 hours. The reaction is diluted with methylene chloride andwashed with 10% HCl followed by water. The extract is dried over sodiumsulfate and concentrated in vacuo. The reaction is best purified bymedium pressure liquid chromatography (MPLC) (i.e., flash chromatographyon silica gel (25 g, 1:1 hexane-ethyl acetate as eluant) produces acontaminated product as determined by ¹ H NMR and flash chromatographyon silica gel (30 g silica, 1:1:1 hexane-ethyl ether-methylene chloride)also produces a contaminated product as determined by ¹ H NMR).M+(CI)=367. ¹ H NMR: 0.64 (3H, d), 1.67 (1H, dd), 1.89 (1H, d), 2.06(1H, m), 2.26 (2H, m), 2.49 (3H, m), 2.72 (1H, dd), 3.05 (1H, t), 5.08(3H, m), 5.92 (2H, s), 6.15 (1H, s), 6.65 (3H, m).

EXAMPLE 564-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-methoxy-5-methyl-8H-2,5a-methano-9-bromo-1-benzoxepin-8-one(111, FIG. 11)

Pyridine (19.0 mg, 0.24 mmols) is added to a stirred solution offutoenone (101)(51 mg, 0.15 mmols) in 2 ml distilled dichloromethane,followed by the addition of a 0.1M solution of bromine (2 ml) at -60° to-78° C. under argon. The reaction is stirred overnight and slowly warmedup from -78 ° C. to room temperature. After 24 h, the reaction isconcentrated in vacuo and purified by MPLC using ethyl acetate on silicagel. The major product identified by TLC is collected and concentratedin vacuo forming a white solid. The solid is recrystallized using ethylacetate, 234.5 mg (95.2%). M+(CI)=419. ¹ H NMR ppm: 0.55 (3H, d), 2.05(1H, m), 2.43 (5H, m), 3.66 (3H, s), 5.19 (1H, t), 5.49 (1H, s), 5.92(2H, s), 6.68 (3H, m).

EXAMPLE 57

Following substantially the same procedure as described in Example 20(however, 2 equivalents of bromine are used),4-(1,3-benzodioxol-6-bromo-5-yl)-2,3,4,5-tetrahydro-7-methoxy-5-methyl-8H-2,5a-methano-9-bromo-1-benzoxepin-8-one(112, FIG. 11) is produced. ¹ H NMR ppm: 0.566 (3H, d), 1.579 (1H, t),2.074 (1H, m), 2.267-2.47 (3H, m), 3.277 (3H, m), 3.662 (3H, s), 5.194(1H, t), 5.494 (1H, s), 5.95 (2H, s), 6.714 (1H, s) 6.959 (1H, s).

EXAMPLE 584-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-methoxy-5-methyl-8H-2,5a-methano-9-allyl-1-benzoxepin-8-one(113, FIG. 12)

Tetrakis (triphenylphosphine)palladium (o) (14.9 mg, 0.013 mmoles) andallyltributyltin (88 Ul, 0.28 mmoles) are added to a stirred solution of4-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-methoxy-5-methyl-8H-2,5a-methano-9-bromo-1-benzoxepin-8-one(111, prepared according to Example 20) in 4 ml of toluene. The reactionis heated to reflux for four and half hours after which the formation ofreaction product is detectable by TLC using ethyl acetate. The reactionis then concentrated in vacuo and purified by MPLC using ethyl acetate.The product is a pale yellow foam (80.6 mg, 38%). M+(CI)=381. ¹ NMR ppm:0.55 (3H, d), 1.70 (1H, t), 2.0 (1H, m), 2.15 (1H, d), 2.31 (21H, m),2.49 (1H, m), 3.16 (2H, dd), 3.64 (3H, s), 5.0 (3H, m), 5.44 (1H, s),5.93 (3H, m), 6.66 (3H, m).

EXAMPLE 594-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-trifluoro-acetyl-5-methyl-8H-2,5a-methano-1-benzoxepin-8-one(114, FIG. 12)

Trifluoroacetic anhydride (85.4 Ul, 0.51 mmoles) in pyridine (3.5 ml) isadded at -40° C. to a stirred solution of4-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-hydroxy-5-methyl-8H-2,5a-methano-1-benzoxepin-8-one(109, as prepared in Example 54)(110.3 mg, 0.34 mmoles). The reaction isstirred at -40° to 0° C. over a three hour period and is then washedwith saturated sodium bicarbonate and dried over sodium sulfate. Thereaction mixture is filtered, concentrated in vacuo, and purified usingMPLC with ethyl acetate. A reddish oil (135.9 mg, 87.6%) is isolated andcharacterized by mass spec. and ¹ H NMR. N+(CI)=405. ¹ H NMR ppm: 0.65(3H, d), 1.75 (1H, t), 2.20 (3H, m), 2.53 (2H, m), 5.1 (1H, t), 5.85(1H, s), 5.93 (2H, s), 6.68 (4H, m).

EXAMPLE 604-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-allyl-5-methyl-8H-2,5-methano-1-benzoxepin-8-one(115, FIG. 12)

Tetrakis (triphenylphosphine)palladium (o) (1.4 mg, 0.002 mmols),lithium chloride (24.2 mg, 0.57 mmols) and 2 ml of THF are added to asolution of4-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-trifluoro-acetyl-5-methyl-8H-2,5a-methano-1-benzoxepin-8-one(114, prepared according to Example 23) (37.5 mg, 0.079 mmols) andallyltributylin (24.5 μl,0.079 mmols) in 1.5 ml THF. The reaction isheated to reflux in an oil bath for five hours. The yellow reactionmixture is diluted with pentane and washed with 10% ammonium hydroxide.The extract is dried over sodium sulfate, filtered and concentrated invacuo. The reaction is purified by MPLC on silica gel using 1:1hexane-ethyl acetate as the eluant. The fractions corresponding to theproduct are combined and concentrated in vacuo to form a pale yellowfoam (19 mg, 68.7%). M+(CI)=367. ¹ H NMR ppm: 0.52 (3H, d), 1.70 (1H,dd), 2.02 (1H, m), 2.07 (1H, d), 2.30 (2H, m), 3.09 (2H, td), 4.98 (1H,t), 5.08 (2H, dd), 5.74 (1H, s), 5.83 (1H, m), 5.93 (2H, s), 6.36 (1H,s), 6.67 (3H, m).

EXAMPLE 614-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-methoxy-5-methyl-8H-2,5a-methano-1-benzoxepin-8-thione(102, FIG. 9)

Lawesson's reagent (119.3 mg, 0.3 mmoles) is added to a stirred solutionof futoenone (200 mg, 0.59 mmoles) in toluene (4 ml). The reaction isheated to 60° C. in an oil bath for 2-3 h. TLC of the reaction mixtureshows almost complete conversion of starting material. The reactionturns from a green to violet upon heating. The reaction is concentratedin vacuo and purified by MPLC on silica gel using ethyl acetate. Apurple foam (154.2 mg, 73.5%) forms upon drying in vacuo. M+(CI)=357. ¹H NMR ppm: 0.59 (3H, d), 1.72 (1H, t), 2.07 (1H, m), 2.21 (1H, d), 2.30(1H, m), 2.43 (1H, m), 2.58 (1H, m), 3.71 (3H, s), 5.08 (1H, t), 5.46(1H, s), 5.92 (2H, s), 6.65 (4H, m).

EXAMPLE 622-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-6-methoxy-7-thioacetyldihydrobenzofuran(104, FIG. 9)

Boron trifluoride- etherate (42.6 μl, 0.35 mmoles) is added to a stirredsolution of4-(1,3-benzodioxol-5-yl)-2,3,4,5-tetrahydro-7-methoxy-5-methyl-8H-2,5a-methano-1-benzoxepin-8-thione(102, prepared according to Example 61) (81.2 mg, 0.23 mmoles) in aceticat anhydride at 0° C. under argon. The reaction changes color frompurple to orange then to an orange-yellow color. After stirring at 0° C.for two hours, the reaction is washed with saturated sodium bicarbonate.The extract is dried over sodium sulfate, filtered, and concentrated invacuo. M+(CI)=459. ¹ H NMR ppm: 1.05 (3H, d), 1.76 (1H, td), 2.05 (3H,s), 2.21 (1H, td), 2.38 (3H, s), 2.74 (1H, dd), 2.98 (1H, td), 3.10 (1H,dd), 3.75 (3H, s), 4.42 (1H, q), 5.02 (1H, m), 5.94 (3H, s), 6.71 (5H,m). Anal. Calcd. for C₂₄ H₂₂ O₄ S: C, 62.87; H, 5.72; S, 7.0. Found: C,62.80; H, 5.75; S, 7.06. (Analytical data C=carbon, H=hydrogen, andS=sulfur).

EXAMPLE 632-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-6-methoxy-7-thioldihydrobenzofuran(106a, FIG. 9)

Methanolic HCl is added to a stirred solution of2-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-6-methoxy-7-thioacetyldihydrobenzofuran (104, prepared asdescribed in Example 62) (33.1 mg, 0.072 mmoles) in 0.25 ml chloroformat 0° C. under argon. Methanolic HCl is generated by addition of acetylchloride to methanol at 0° C. The reaction is stirred an 0° C. for onehour and is then allowed warm to room temperature overnight. Thereaction is monitored by TLC and after 48 hours is stopped. The mixtureis washed with saturated sodium bicarbonate, followed by water and driedover sodium sulfate. The product (21.9 mg, 81%) is purified by MPLC onsilica gel using ethyl acetate. M+(CI)=374. ¹ H NMR ppm: 1.05 (3H, d),1.81 (1H, td), 2.39 (1H, td), 2.71 (1H, dd), 2.82 (1H, m), 3.05 (1H,dd), 3.76 (1H, s), 3.79 (3H, s), 4.49 (1H, q), 5.98 (2H, s), 6.71 (5H,m).

EXAMPLE 642-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-6-methoxy-7-thiomethyldihydrobenzofuran(106b)

Iodomethane (11.3 mg, 0.08 mmols) and potassium carbonate (21.9 mg,0.159 mmols) with a small amount of 18-crown-6 ether are added to astirred solution of2-[3-hydroxy-2-(1,3-benzodioxol-5-yl)butane]-6-methoxy-7-thioldihydrobenzofuran(106a, prepared as described in Example 63) (20 mg, 0.053 mmols) in THF(1.5 ml). The reaction is stirred an room temperature for six hoursunder argon, afterwhich the reaction is washed with sodium bicarbonatefollowed by water. The extract is dried over sodium sulfate, filtered,and concentrated in vacuo. The reaction is purified by MPLC using 1:1hexane-ethyl acetate, and an oil is isolated (48.3%). M+(CI)=390.

EXAMPLE 654-(1,3-dihydroxyphenyl)-2,3,4,5-tetrahydro-7-methoxy-5-methyl-8H-2,5a-methano-1-benzoxepin-8-one(116, FIG. 13)

Triphenylcarbenium tetrafluoroborate (359 mg, 1.09 mmols) is added to astirred solution of futoenone (101) (200 mg, 0.588 mmols) in 2 mldistilled dichloromethane. The reaction is stirred for one hour an 0° C.The flask is then warmed no room temperature and stirred for anadditional 24 hours. The reaction is monitored with TLC. After thestarting material was completely consumec (approximately 24 h), thesolvent is removed :n vacuo and the reaction mixture purified usingflash column chromatography on silica (50 g, ethyl acetate) to produce amixture as a product (0.1871 g, 97%)(as determined by 1H NMR). Thereaction mixture is dissolved in 2 ml chloroform and a solution ofmethanolic HCl is added dropwise to the flask. After stirring for 1 h at0° C., the mixture is warmed to room temperature overnight. No change isseen in the mixture by TLC after 12 h. The reaction is washed usingsodium bicarbonate followed by water. The extract is concentrated invacuo and triturated with methylene chloride to form white crystals 0.12g (70%). M+(CI)=329. ¹ H NMR ppm: 0.39 (3H, d), 1.72 (1H, t), 2.1-2.3(5H, m), 3.62 (3H, s), 5.03 (1H, t), 5.53 (1H, s), 5.68 (1H, s), 6.60(1H, dd), 6.70 (1H, d), 6.81 (1H, d).

EXAMPLE 664-(1,3-dimethoxyphenyl)-2,3,4,5-tetrahydro-7-methoxy-5-methyl-8H-2,5a-methano-1-benzoxepin-8-one(117, FIG. 13)

Potassium hydroxide (71.8 mg, 1.28 mmols) and 18-crown-6 ether (45.6 mg,0.17 mmols) are added to a stirred solution of4-(1,3-dihydroxyphenyl)-2,3,4,5-tetrahydro-7-methoxy-5-methyl-8H-2,5a-methano-1-benzoxepin-8-one(116, prepared according to Example 65) (70 mg, 0.21 mmols) in 1 mldistilled THF. The reaction mixture turns blue. Upon addition ofiodomethane (53 μl, 0.85 mmols), the reaction turns purple. After 30minutes, the reaction is washed with 10% HCl followed by water. Thereaction mixture turns yellow and is dried over sodium sulfate. Thereaction is purified using MPLC on silica gel (15 g, 1:1 hexane-ethylacetate), 53.3 mg (79%). M+(CI)=357. ¹ H NMR ppm: 0.58 (3H, d), 1.74(1H, t), 2.04 (1H, m), 2.20 (1H, d), 2.3 (2H, m), 2.55 (1H, m), 3.676(3H, s), 3.87 (6H, d), 5.04 (1H, t), 5.49 (1H, s), 5.79 (1H, s), 6.69(1H, s), 6.72 (1H, d), 6.82 (1H, d).

Referring now to FIGS. 14a, 14b, 15a, 15b, 16a, and 16b, many futoenonederivative compounds have been synthesized according to the schemesshown in FIGS. 9-13 and discussed in Examples 12 to 30 and many otherfutoenone derivative compounds are readily synthesizable via the same orsimilar schemes. Several of these compounds have been tested for theirantagonist activity for PAF induced platelet aggregation and for theirinhibition of the production of leukotrienes via the 5-lipoxygenasepathway in PMN leukocytes or monocytes according to the proceduresdescribed above. FIGS. 14b and 15b show that small concentrations offutoenone and futoenone derivative compounds exhibit potent PAFantagonist activity and FIG. 16b shows that small concentrations offutoenone derivative compounds exhibit potent 5-lipoxygenase inhibition.Therefore, these compounds would be beneficial for the treatment of thelarge number of diseases and disorders that are mediated by leukotrienesand PAF.

FIGS. 17 and 18 disclose a procedure for synthesizing futoenone andfutoenone derivative compounds. Benzyl bromide (BnBr) is used to protectisovanillin (201) by reaction using phase transfer conditions to yield3-benzyloxy-4-methoxybenzaldehyde (202). Oxidation of3-benzyloxy-4-methoxybenzaldehyde (202) with m-chloroperbenzoic acidfollowed by hydrolysis in refluxing methanol yields3-benzyloxy-4-methoxyphenol (203). The phenol is placed in toluene andthe suspension is treated with n-butyl-lithium to form a precipitate.1,4-dibromobutene is then added to the reaction and the contents areheated to reflux overnight to form vinylbenzofuran (206). An ester (207)is formed using a Horner-Emmons modified Wittig reaction and issubsequently reduced to the allylic alcohol (208) usingdiisobutylaluminum hydride. The allylic alcohol can then be epoxidizedin a Sharpless epoxidation to form2-(2,3'-epoxybutanol)-7-benzyloxy-6-methoxydihydrobenzofuran (209).

The use of the Sharpless epoxidation provides the benefit ofenantiomeric selectively at the chiral center indicated by the star.FIG. 18 shows the epoxide (209) can then be opened using a substitutedaryl or heteroaryl Grignard or Lewis acid to form, for example, thetrimethyoxyphenyl derivative2-[3-hydroxy-3-methoxy-2-(1,3-benzodioxol-5-yl)propane]-7-hydroxy-6-methoxydihydrobenzofuran(210) (this is reaction scheme B in FIG. 18). Alternatively, the primaryalcohol formed from epoxide opening of (209) can be removed byconversion to a good leaving group followed by treatment with lithiumsuperoxide, or alkylated with various groups such as methyl iodide, toform (210) (this is reaction scheme A in FIG. 18 which involves the useof lithium triethylborohydride). To prepare derivatives of futoenonefrom2-[3-hydroxy-3-methoxy-2-(1,3-benzodioxol-5-yl)propane]-7-hydroxy-6-methoxydihydrobenzofuran(210) would simply involve ring closure following the procedure ofOgisa.

Formation of the epoxide (209) in FIG. 17 should provide an easy way tomodify the top aromatic ring on the futoenone skeleton. The3,4,5-trimethoxyphenyl magnesium bromide can be replaced by othersubstituted aryl or heteroaryl (such as furyl, thienyl, pyridyl, orindolyl) Grignard reagents to prepare the corresponding aryl substitutedfutoenone derivatives. The top aromatic ring of the futoenone skeletoncould be substituted with hydrogen, lower alkyl, lower alkenyl, loweralkynyl, lower alkoxy, methylene dioxy, lower alkylthio, hydroxy, loweralkyl sulfonyl, hydroxy lower alkyl sulfonyl, lower alkyl sulfinyl,hydroxy lower alkylsulfinyl, aminoalkylsulfonyl, acyloxyalkylsulfonyl,acylamidoalkylsulfonyl, halogen, haloalkyl, alkoxyalkyl, alkylthioalkyl,or the like. Additionally, as shown in FIG. 18, the hydroxy at the endof 2-(2,3'-epoxybutanol)-7-benzyloxy-6-methoxydihydrobenzofuran (209)provides a handle by which the R group can be selectively modified.While FIG. 18 shows the formation of futoenone derivative compounds withthe R group denoted as a hydrogen or methoxy it should be understoodthat the R group can be replaced with other alkoxy groups as well asalkylthio groups.

The following Examples provide further discussion related to thesynthetic pathway for producing futoenone analogs which is shown inFIGS. 17 and 18.

EXAMPLE 67 3-benzyloxy-4-methoxybenzaldehyde (202, FIG. 17)

18--Crown-6 ether (0.14 g, 0.00052 mols) and potassium hydroxide (1.35g, 0.024 mols) is added to a stirred solution of isovanillin (201) (2.0g, 0.013 mols) in THF (20 ml) at 0° C. The reacton becomes cloudy andturns bright yellow. Benzyl bromide (1.69 ml, 0.0143 mols) is addeddropwise to the reaction at 0° C. After one hour, the ice bath isremoved and the reaction is stirred at room temperature overnight. Thereaction is diluted with ethyl acetate and washed with water and 10% HClfollowed by brine solution. The organic extract is dried over sodiumsulfate, filtered, concentrated and dried in vacuo no a yellowcrystalline solid (3.0471 g, 96.9%).

EXAMPLE 68 3-benzyloxy-4-methoxyphenol (203, FIG. 17)

3-chloroperoxybenzoic acid (9.9 g, 0.0343 mols), in small portions, isadded to a stirred solution of 3-benzyloxy-4-methoxybenzaldehyde (201,prepared as described in Example 66) (7.57 g, 0.0313 mols) indicloromethane (100 ml) over a thirty minute period With vigorousshirring. The reaction flask is fitted with a condensor and the contentsis heated to reflux for six hours and monitored by TLC using 2:1hexane-ethyl acetate as eluant. The reaction is filtered off the3-chlorobenzoic acid (which precipitates out of solution) and thefiltrate is washed with saturated sodium bicarbonate followed by waterand dried in vacuo to an oil which eventually solidifies. The solid issubsequently dissolved in distilled methanol (80 ml) and heated toreflux under nitrogen. TLC using hexane-ethyl acetate as the eluantshows almost complete conversion after two hours and forty five minutes.The solvent is removed in vacuo no produce a dark oil which isredissolved in a small amount of ethyl acetate and purified by columnchromatography on silica gel (2:1 hexane-ethyl acetate as eluant). Themajor fraction from the column is combined and concentrated in vacuo toa solid (4.68 g, 64.9%).

EXAMPLE 69 2-vinyl-7-benzyloxy-6-methoxydihydrobenzofuran (204, FIG. 17)

Using the procedure of Bigi et al, Tetrahedron, 39, 169 (1983), thebenzofuran system is constructed. N-butyl lithium (3.95 ml of a 2.2Msolution) is added to a solution of 3-benzyloxy-4-methoxyphenol (203,prepared as described in Example 32)(2.0 g, 0.0087 mols) in dry toluene.Upon addition of the n-butyl lithium, a precipitate falls out ofsolution. After all the n-butyl lithium is added, the reaction isstarred for 15-20 minutes at room temperature. Subsequently, thereaction is heated to reflux for twenty one hours. The reaction is thendiluted with ethyl acetate and washed with 10% HCl and water. Theextract is dried over sodium sulfate. The crude reaction mixture ispurified by flash column chromotography using 2:1 hexane-ethyl acetateas eluant to obtain two major products which are (1) unreacted startingmaterial and (2) product (0.979 g, 37.6%)

EXAMPLE 70 2-(2'-hydroxyethane)-7-benzyloxy-6-methoxydihydrobenzofuran(205, FIG. 17)

BH₃.THF complex (4.8 ml, 0.0048 mols) is added to a stirred solution of2-methyl-2-butene (1.02 ml, 0.0096 mmols) in distilled THF (4 ml) at 4°C. under nitrogen. The reaction is stirred at 4° C. for one hour.2-vinyl-7-benzyloxy-6-methoxydihydro benzofuran (204,described above inExample 69) (0.896 g, 0.0032 mols) in distilled THF (4 ml) is addedrapidly dropwised no the shirred reaction. After five minutes, thereaction is removed from the ice bath and sniffed at room temperaturefor three and one half hours while being monitored every half hour byTLC using 1:1 hexane-ethyl acetate as eluant). The reaction is thencooled no 4° C. and 10% sodium hydroxide (2.8 ml) is added slowlydropwise to the reaction while keeping the intenal temperature below 20°C. The cooling bath is removed after one hour and the reaction isdiluted with ethyl acetate and washed with water and 10% HCl. Theextract is dried over sodium sulfate and purified by columnchromatography on silica gel using 1:1 hexane-ethyl acetate as eluant toproduce an off-white solid (0.4942 g, 5.15%).

EXAMPLE 71 2-(acetaldehyde)-7-benzyloxy-6-methoxydihydro benzofuran(206, FIG. 17)

The following oxidationis performed using Dess-Martin conditions (see,Dess et al, J. Org. Chem., 48, 4156 (1983)). A solution of2-(2'-hydroxyethane)-7-benzyloxy-6-methoxydihydrobenzofuran(205,described in Example 70) (166.8 mg, 0.56 mmols) in dichloromethane(2 ml) is added to a stirred solution of periodinane (259.3 mg, 0.612mmols) in dichloromethane (4 ml). The reaction is shirred forty fiveminutes while being monitored every fifteen minutes by TLC using 1:1hexane-ethyl acetate as eluant. The reaction is then diluted withaqueous sodium bicarbonate and sodium thiosulfate. The extract is driedover sodium sulfate and the reaction is purified using columnchromatography on silica gel (1:1 hexane-ethyl acetate) to a colorlessoil (90.6 mg, 54.3%).

EXAMPLE 72 2-(ethyl crotonate)-7-benzyloxy-6-methoxydihydrobenzofuran(207, FIG. 17)

Triethylamine (53.1 μl, 0.268 mmols) is added to a stirred solution ofsodium hydride (6.44 mg, 0.268 mmols) in THF (4 ml) at room temperatureunder nitrogen. The mixture is stirred for fifteen minutes before asolution of 2-(acetaldehyde)-7-benzyloxy-6-methoxydihydrobenzofuran(206, prepared as described in Example 71) (80 mg, 0.268 mmols) in THF(2 ml) is added dropwise slowly to the reaction. The reaction turns darkupon addition of the aldehyde and is stirred for an additional tenminutes at room temperature after which TLC with 1:1 hexane-ethylacetate shows no additional aldehyde present. Several drops of ethanolare added no react with any unreacted sodium hydride. The reaction issubsequently diluted with ethyl acetate, washed with water, and driedover sodium sulfate. The extract is filtered and concentrated in vacuowith crude ¹ H NMR showing the desired product. Further purification isperformed by column chromatography on silica gel (1:1 hexane-ethylacetate) to yield a colorless oil (85.8 mg, 87%).

EXAMPLE 73 2-(2'-buten-4'-ol)-7-benzyloxy-6-methoxydihydrobenzofuran(208, FIG. 17)

Diisobutylaluminum hydride (DIBAH) (0.2 ml, 0.2 mmol) is added to astirred solution of2-(ethylcrotonate)-7-benzyloxy-6-methoxydihydrobenzofuran (207, preparedas described in Example 72) (66.9 mg, 0.182 mmols) in distilleddichloromethane (4 ml) at -78° C. under nitrogen. The reaction isstirred thirty minutes, quenched by the addition of ethyl acetate (2ml), and allowed to warm to room temperature. The reaction is dilutedwith diethyl ether (4 ml) and extracted with an aqueous solution ofsodium potassium tartrate and brine. The extract is dried over sodiumsulfate and filtered through celite. The reaction mixture is purified bycolumn chromatography on silica gel using 1:1 hexane-ethyl acetate aseluant to produce a yellow oil (43.7 mg, 73.7%).

EXAMPLE 74 2-(2',3'-epoxybutanol)-7-benzyloxy-6-methoxydihydrobenzofuran(209, FIG. 17)

This compound has not been prepared but can be prepared by Sharplessepoxidation methodology (see, Katsuki et al., J. Amer. Chem. Soc., 102,5974 (1980). Dichloromethane should be placed in a round bottom flaskand cooled to -23° C. in a dry ice/carbontetrachloride bath. Thefollowing are then added sequentially by syringe with vigorous stirring:titanium tetraisopropoxide and L(+)-diethyl tartrate. This mixture wouldthen be stirred for five minutes followed by the addition of2-(2'-buten-4'-ol)-7-benzyloxy-6-methoxydihydro benzofuran (208,prepared as described in Example 37) and a solution of dichloromethaneand t-butylhydroperoxide. The reaction can be stored overnight in thefreezer at -20° C. in a sealed reaction vessel. The flask would then becooled to -23° C. and 10% aqueous tartaric acid solution would be added.After thirty minutes, the bath would be removed and the reaction wouldbe stirred for one hour. The organic layer would be washed with waterand dried over sodium sulfate.

EXAMPLE 752-(2',3'-epoxy-4-methoxybutane)-7-benzyloxy-6-methoxydihydrobenzofuran

Potassium hydroxide, 18-crown-6 ether followed by iodomethane would beadded to a stirred solution of2-(2',3'-epoxy-4-methoxybutane)-7-benzyloxy-6-methoxydihydrobenzofuran(209, prepared as described in Example 74) in THF. The reaction would bemonitored by TLC until the starting materials are consumed. The reactionwould then be washed with water, 10% HCl and brine. The organic extractwould then be dried over sodium sulfate and purification would beperformed using column chromatography on silica gel using hexane-ethylacetate as the eluant.

EXAMPLE 76 2-[3-hydroxy-3-methoxy-2-(1,3-benzodioxol-5-yl)propane-7-hydroxy-6-methoxydihydrobenzofuran (210, FIG. 18)

Ring opening of2-(2',3'-epoxy-4-methoxybutane)-7-benzyloxy-6-methoxydihydrobenzofuran(209, prepared as described in Example 74) would be performed byreaction with a Grignard reagent of 4-bromo-1,2-(methylenedioxy)benzenein anhydrous ether. The reaction would be acidified, washed withadditional ether and dried over sodium sulfate. Purification wouldinvolve column chromatography on silica gel using a hexane-ethyl acetatesolvent system.

EXAMPLE 77 Futoenone Analogs

The cyclization of2-[3-hydroxy-3-methoxy-2-(1,3-benzodioxol-5-yl)propane)-7-hydroxy-6-methoxydihydrobenzofuran(210) would involve using the methodology previously performed by Ogisoet al., Chem. Pharm. Bull., 18, 105 (1970), that article being hereinincorporated by reference.

It is anticipated that the compounds of the present invention can beprovided to human and animal patients in pharmaceutical doses for thepurpose of inhibiting PAF and 5-lipoxygenase activity and, thereby,provide treatment or prevention of PAF and leukotriene disorders anddiseases. The dose level will depend on a variety of factors includingthe activity of the specific compound employed and the age, sex, andphysical condition of the subject being treated. It is anticipated thatthe dose level will be on the order of 0.1-30 mg/kg of body weight perday; however, larger and smaller amounts are anticipated. The compoundsof the present invention can be administered orally, by injection, bysuppository, or by any other pharmaceutically acceptable route. As iswell understood in the art, the compounds can be administered as saltsor the like and can be administered in conjunction with suitable inertbinders, excipients, elixirs, emulsions, oils, suspensions,microencapsules, intradermal devices, ointments (topicaladministration), lubricating agents, and the like.

While the invention has been described in terms of its preferredembodiments wherein synthetic neolignan derivative compounds have beenproduced and used as PAF and 5-lipoxygenase antagonists, those skilledin the art will recognize that the invention can be practiced withmodification within the spirit and scope of the appended claims.

We claim:
 1. A compound of the formula: ##STR4## wherein R¹ is selectedfrom the group consisting of hydrogen, haloloweralkyl, loweralkenyl,loweralkynyl, --CONR² R³ --COR², --CO₂ R², --CH₂ OR², --CH₂ NR² R³,--CH₂ Sr², and wherein Ar and Ar¹ are the same or different from eachother and are substituted phenyl of the formula: ##STR5## where R⁴ -R⁸independently are selected from the group consisting of --NO₂, --NR² R³,--NR² COR³, --N(OH)COR², --NR² CONR² R³, --NR² CON(OH)R², --CO₂ R²,--OC(O)R², --R² N(OH)CONR² R³, --CONR² R³, --CON(OH)R², --OR², --SR²,--R⁹, --R⁹ NR² CON(OH)R², --R⁹ N(OH)CONR² R³, --(C₅ H₄ N), --OR⁹O(CO)N(COR⁹)R⁹, --(C₅ H₄ N)R⁹ R¹⁰, --OR⁹ O(CO)N(CO₂ R⁹)R⁹, --OR⁹ OH,--SR⁹ OH, --OR⁹, --SR⁹, --X, --hydrogen, --R², --CN, --R⁹ NR² R³,--SOR⁹, --SO₂ R⁹, --SOR⁹ OH, --SO₂ R⁹ OH, --OR⁹ OR², and --O₂ CNR² R³,and wherein R² and R³ independently represent C₁₋₁₀ alkyl, alkenyl,alkynyl, aryl, aralkyl, and hydrogen, wherein R⁹ is selected from thegroup consisting of haloalkyl, loweralkyl, loweralkenyl, lower alkynyl,aralkyl, and aryl, and wherein R¹⁰ is an organic or inorganic anion andX is halogen,wherein a hyphen preceding R² or R⁹ indicates that the R²or R⁹ substituent is attached to the substituted phenyl, and wherein aN, O or S adjacent to R² or R⁹ indicates that the N, O, or S is bondeddirectly to the R² or R⁹ substituent.
 2. The compound of claim 1 whereinR¹ is H.
 3. The compound of claim 1 wherein R⁴ -R⁸ are selected from thegroup consisting of --CON(OH)R², --N(OH)COR², and --NR² CON(OH)R². 4.The compound of claim 1 wherein R⁴ -R⁸ are --R⁹ N (OH) CONR² R³.
 5. Thecompound of claim 1 wherein R⁴ -R⁸ are --R⁹ NR² CON(OH)R².
 6. Thecompound of claim 1 wherein R⁴ -R⁸ are --R² N(OH)CONR² R³.
 7. Thecompound of claim 1 wherein R⁴ -R⁸ are selected from the groupconsisting of --OR⁹, --SR⁹, --OR², --SR², and --OR⁹ OR².
 8. The compoundof claim 1 wherein R⁴ -R⁸ are selected from the group consisting ofhydrogen, --SO₂ R⁹, --NR² R³ and --R⁹ NR² R³.
 9. The compound of claim 1wherein R² and R³ are independently selected from the group consistingof hydrogen and C₁₋₁₀ alkyl.
 10. The compound of claim 1 wherein R² andR³ are independently selected from the group consisting of C₁₋₁₀ alkenyland alkynyl.
 11. The compound of claim 1 wherein R⁹ is lower alkyl. 12.The compound of claim 1 wherein R⁹ is lower alkenyl or lower alkynyl.13. The compound of claim 1 wherein R¹⁰ is an organic anion.
 14. Thecompound of claim 1 wherein R¹⁰ is an inorganic anion.
 15. A method ofinhibiting PAF induced platelet aggregation in a patient wherein saidmethod comprises administering to the patient an effective amount of acompound of the formula: ##STR6## wherein R¹ is selected from the groupconsisting of hydrogen, haloloweralkyl, loweralkenyl, loweralkynyl,--CONR² R³ --COR², --CO₂ R², --CH₂ OR², --CH₂ NR² R³, --CH₂ SR², andwherein Ar and Ar¹ are the same or different from each other and aresubstituted phenyl of the formula: ##STR7## where R⁴ -R⁸ independentlyare selected from the group consisting of --NO₂, --NR² R³, --NR² COR³,--N(OH)COR², --NR² CONR² R³, --NR² CON(OH)R², --CO₂ R², --OC(O)R², --R²N(OH)CONR² R³, --CONR² R³, --CON(OH)R², --OR², --SR², --R⁹, --R⁹ NR²CON(OH)R², --R⁹ N(OH)CONR² R³, --(C₅ H₄ N), --OR⁹ O(CO)N(COR⁹)R⁹, --(C₅H₄ N)R⁹ R¹⁰, --OR⁹ O(CO)N(CO₂ R⁹)R⁹, --OR⁹ OH, --SR⁹ OH, --OR⁹, --SR⁹,--X, --hydrogen, --R², --CN, --R⁹ NR² R³, --SOR⁹, --SO₂ R⁹, --SOR⁹ OH,--SO₂ R⁹ OH, --OR⁹ OR², and --O₂ CNR² R³, and wherein R² and R³independently represent C₁₋₁₀ alkyl, alkenyl, alkynyl, aryl, aralkyl,and hydrogen, wherein R⁹ is selected from the group consisting ofhaloalkyl, loweralkyl, loweralkenyl, lower alkynyl, aralkyl, and aryl,and wherein R¹⁰ is an organic or inorganic anion and where X ishalogen,wherein a hyphen preceding R² or R⁹ indicates that the R² or R⁹substituent is attached to the substituted phenyl, and wherein a N, O orS adjacent to R² or R⁹ indicates that the N, O, or S is bonded directlyto the R² or R⁹ substituent.
 16. A method of inhibiting the productionof leukotrienes in a patient wherein said method comprises administeringto the patient an effective amount of a compound of the formula:##STR8## wherein R¹ is selected from the group consisting of hydrogen,haloloweralkyl, loweralkenyl, loweralkynyl, --CONR² R³ --COR², --CO₂ R²,--CH₂ OR², --CH₂ NR² R³, --CH₂ SR², and wherein Ar and Ar¹ are the sameor different from each other and are substituted phenyl of the formula:##STR9## where R⁴ -R⁸ independently are selected from the groupconsisting of --NO₂, --NR² R³, --NR² COR³, --N(OH)COR², --NR² CONR² R³,--NR² CON(OH)R², --CO₂ R², --OC(O)R², --R² N(OH)CONR² R³, --CONR² R³,--CON(OH)R², --OR², --SR², --R⁹, --R⁹ NR² CON(OH)R², --R⁹ N(OH)CONR² R³,--(C₅ H₄ N), --OR⁹ O(CO)N(COR⁹)R⁹, --(C₅ H₄ N)R⁹ R¹⁰, --OR⁹ O(CO)N(CO₂R⁹)R⁹, --OR⁹ OH, --SR⁹ OH, --OR⁹, --SR⁹, --X, --hydrogen, --R², --CN,--R⁹ NR² R³, --SOR⁹, --SO₂ R⁹, --SOR⁹ OH, --SO₂ R⁹ OH, --OR⁹ OR², and--O₂ CNR² R³, and wherein R² and R³ independently represent C₁₋₁₀ alkyl,alkenyl, alkynyl, aryl, aralkyl, and hydrogen, wherein R⁹ is selectedfrom the group consisting of haloalkyl, loweralkyl, loweralkenyl, loweralkynyl, aralkyl, and aryl, and wherein R¹⁰ is an organic or inorganicwhere X is halogen,wherein a hyphen preceding R² or R⁹ indicates thatthe R² or R⁹ substituent is attached to the substituted phenyl, andwherein a N, O or S adjacent to R² or R⁹ indicates that the N, O, or Sis bonded directly to the R² or R⁹ substituent.
 17. A method ofinhibiting the production of both PAF induced platelet aggregation andthe production of leukotrienes in a patient wherein said methodcomprises administering to the patient an effective amount of a compoundof the formula: ##STR10## wherein R¹ is selected from the groupconsisting of hydrogen haloloweralkyl, loweralkenyl, loweralkynyl,--CONR² R³ --COR², --CO₂ R², --CH₂ OR², --CH₂ NR² R³, --CH₂ SR², andwherein Ar and Ar¹ are the same or different from each other and aresubstituted phenyl of the formula: ##STR11## where R⁴ -R⁸ independentlyare selected from the group consisting of --NO₂, --NR² R³, --NR² COR³,--N(OH)COR², --NR² CONR² R³, --NR² CON(OH)R², --CO₂ R², --OC(O)R², --R²N(OH)CONR² R³, --CONR² R³, --CON(OH)R², --OR², --SR², --R⁹, --R⁹ NR²CON(OH)R², --R⁹ N(OH)CONR² R³, --(C₅ H₄ N), --OR⁹ O(CO)N(COR⁹)R⁹, --(C₅H₄ N)R⁹ R¹⁰, --OR⁹ O(CO)N(CO₂ R⁹)R⁹, --OR⁹ OH, --SR⁹ OH, --OR⁹, --SR⁹,--X, --hydrogen, --R², --CN, --R⁹ NR² R³, --SOR⁹, --SO₂ R⁹, --SOR⁹ OH,--SO₂ R⁹ OH, --OR⁹ OR², and --O₂ CNR² R³, and wherein R² and R³independently represent C₁₋₁₀ alkyl, alkenyl, alkynyl, aryl, aralkyl,and hydrogen, wherein R⁹ is selected from the group consisting ofhaloalkyl, loweralkyl, loweralkenyl, lower alkynyl, aralkyl, and aryl,and wherein R¹⁰ is an organic or inorganic anion and where X ishalogen,wherein a hyphen preceding R² or R⁹ indicates that the R² or R⁹substituent is attached to the substituted phenyl, and wherein a N, O orS adjacent to R² or R⁹ indicates that the N, O, or S is bonded directlyto the R² or R⁹ substituent.
 18. The method of claims 15, 16, or 17,wherein R¹ is H.
 19. The method of claims 15, 16, or 17, wherein R⁴ -R⁸are selected from the group consisting of --CON(OH)R², --N(OH)COR², and--NR² CON(OH)R².
 20. The method of claims 15, 16, or 17, wherein R⁴ -R⁸are --R⁹ N(OH)CONR² R³.
 21. The method of claims 15, 16, or 17, whereinR⁴ -R⁸ are --R⁹ NR² CON(OH)R².
 22. The method of claims 15, 16, or 17,wherein R⁴ -R⁸ are --R² N(OH)CONR² R³.
 23. The method of claims 15, 16,or 17, wherein R⁴ -R⁸ are selected from the group consisting of --OR⁹,--SR⁹, --OR², --SR², and --OR⁹ OR².
 24. The method of claims 15, 16, or17, wherein R⁴ -R⁸ are selected from the group consisting of hydrogen,--SO₂ R⁹, --NR² R³ and --R⁹ NR² R³.
 25. The method of claims 15, 16, or17, wherein R² and R³ are independently selected from the groupconsisting of hydrogen and C₁₋₁₀ alkyl.
 26. The method of claims 15, 16,or 17, wherein R² and R³ are independently selected from the groupconsisting of C₁₋₁₀ alkenyl and alkynyl.
 27. The method of claims 15,16, or 17, wherein R⁹ is lower alkyl.
 28. The method of claims 15, 16,or 17, wherein R⁹ is lower alkenyl or lower alkynyl.
 29. The method ofclaims 15, 16, or 17, wherein R¹⁰ is an organic anion.
 30. The method ofclaims 15, 16, or 17, wherein R¹⁰ is an inorganic anion.